subject:(protein dynamics)

University of Notre Dame

1. John S Zintsmaster. A Network of Residues Relevant to Enzymatic Function in Pin1: A Nuclear Magnetic Resonance Spectroscopy and Molecular Dynamics Approach</h1>.

Degree: PhD, Chemistry and Biochemistry, 2013, University of Notre Dame

URL: https://curate.nd.edu/show/73666397w5f

► Proteins are in constant motion and these motions impact their function. This thesis attempts to use simple perturbative techniques to track the changes in… (more)

▼ Proteins are in constant motion and these motions impact their function. This thesis attempts to use simple perturbative techniques to track the changes in dynamics upon disrupting the native state of a protein. The protein studied within this thesis is the Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1). Pin1’s function has been extensively studied (Lu 1996) (Ranganathan 1997) (Zhou 1999) (Verdecia 2000) (Wintjens 2001) (Bayer 2003) (Jacobs 2003) (Mueller 2011), yet a single, all-encompassing mechanistic explanation has not been provided. The dynamics of Pin1 has been shown to be closely related to catalysis and function (Namanja 2007) (T. Peng 2007) (Namanja 2011). Thus, Pin1 is an ideal candidate for both a toy system for studying different aspects of the relation between protein dynamics and function as well as a worthwhile protein for studying its specific, practically important functional mechanism. This thesis utilizes a wide variety of experimental and computer based techniques to study the dynamics of Pin1 over timescales ranging from ps to ms. First a novel study of ligand dynamics during catalysis is presented. These NMR experiments are completed at natural isotopic abundance and monitor the μs-ms dynamics of an enzyme-substrate pair. This work represents the first ever study of ligand relaxation dispersion measurements at natural isotopic abundance (Zintsmaster 2008).Next, a brief look at the application of a Gaussian Network Model (GNM) (Bahar 1997) to monitor changes in dynamics upon mutation/deletion is presented. GNM flexibility profiles provide a quick, qualitative means for looking at changes in flexibility upon changes in 3-dimensional structure. Experimental data is compared to the GNM profiles and a good agreement between experiment and GNM is seen. This section will focus on the study of the WW domain of Pin1. Chapter 6 addresses the issue of domain-domain coupling. Pin1 is a two domain protein connected by a flexible 10 residue linker. First NMR order parameters from experiment and MD simulations are compared in an effort to scrutinize the results of both simulation and experiment. Next, the conditions with the greatest degree of agreement are used to simulate the dynamics of full length Pin1 vs. the two isolated domains, the WW domain and the PPIase domain. It is hypothesized that the difference in dynamics of these two simulations can shed light on the weak interactions contributing to domain-domain coupling in full length Pin1. Analysis of these differences dynamic changes at sites that coincide with those undergoing changes upon substrate binding. The last chapter, Chapter 7, deals with MD simulations of three Pin1 single residue mutants. The first two mutants, C113A (Winkler 2000) and T152A (Mueller 2011), have been previously shown to inactivate enzymatic activity in Pin1. Furthermore, Winkler et al. have shown that in crystal structures of Par14, a close relative of human Pin1, an extended hydrogen bonding network can be seen stretching from T152 to… Advisors/Committee Members: Steven Corcelli, Committee Member, Dan Gezelter, Committee Member, Masaru K. Kuno, Committee Member.

Subjects/Keywords: protein dynamics; pin1

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APA (6^th Edition):

Zintsmaster, J. S. (2013). A Network of Residues Relevant to Enzymatic Function in Pin1: A Nuclear Magnetic Resonance Spectroscopy and Molecular Dynamics Approach</h1>. (Doctoral Dissertation). University of Notre Dame. Retrieved from https://curate.nd.edu/show/73666397w5f

Chicago Manual of Style (16^th Edition):

Zintsmaster, John S. “A Network of Residues Relevant to Enzymatic Function in Pin1: A Nuclear Magnetic Resonance Spectroscopy and Molecular Dynamics Approach</h1>.” 2013. Doctoral Dissertation, University of Notre Dame. Accessed August 24, 2019. https://curate.nd.edu/show/73666397w5f.

MLA Handbook (7^th Edition):

Zintsmaster, John S. “A Network of Residues Relevant to Enzymatic Function in Pin1: A Nuclear Magnetic Resonance Spectroscopy and Molecular Dynamics Approach</h1>.” 2013. Web. 24 Aug 2019.

Vancouver:

Zintsmaster JS. A Network of Residues Relevant to Enzymatic Function in Pin1: A Nuclear Magnetic Resonance Spectroscopy and Molecular Dynamics Approach</h1>. [Internet] [Doctoral dissertation]. University of Notre Dame; 2013. [cited 2019 Aug 24]. Available from: https://curate.nd.edu/show/73666397w5f.

Council of Science Editors:

Zintsmaster JS. A Network of Residues Relevant to Enzymatic Function in Pin1: A Nuclear Magnetic Resonance Spectroscopy and Molecular Dynamics Approach</h1>. [Doctoral Dissertation]. University of Notre Dame; 2013. Available from: https://curate.nd.edu/show/73666397w5f

Hong Kong University of Science and Technology

2. Unarta, Ilona Christy. Elucidating protein dynamics and protein-protein interactions using computer modeling and simulations.

Degree: 2017, Hong Kong University of Science and Technology

URL: https://doi.org/10.14711/thesis-991012536069503412 ; http://repository.ust.hk/ir/bitstream/1783.1-88414/1/th_redirect.html

► Biological molecules are complex molecules typically consisting of a few thousand atoms. These molecules interact and undergo conformational change to perform biological function. This thesis… (more)

Subjects/Keywords: Proteins; Dynamics; Computer simulation; Protein-protein interactions

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APA (6^th Edition):

Unarta, I. C. (2017). Elucidating protein dynamics and protein-protein interactions using computer modeling and simulations. (Thesis). Hong Kong University of Science and Technology. Retrieved from https://doi.org/10.14711/thesis-991012536069503412 ; http://repository.ust.hk/ir/bitstream/1783.1-88414/1/th_redirect.html

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Unarta, Ilona Christy. “Elucidating protein dynamics and protein-protein interactions using computer modeling and simulations.” 2017. Thesis, Hong Kong University of Science and Technology. Accessed August 24, 2019. https://doi.org/10.14711/thesis-991012536069503412 ; http://repository.ust.hk/ir/bitstream/1783.1-88414/1/th_redirect.html.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Unarta, Ilona Christy. “Elucidating protein dynamics and protein-protein interactions using computer modeling and simulations.” 2017. Web. 24 Aug 2019.

Vancouver:

Unarta IC. Elucidating protein dynamics and protein-protein interactions using computer modeling and simulations. [Internet] [Thesis]. Hong Kong University of Science and Technology; 2017. [cited 2019 Aug 24]. Available from: https://doi.org/10.14711/thesis-991012536069503412 ; http://repository.ust.hk/ir/bitstream/1783.1-88414/1/th_redirect.html.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Unarta IC. Elucidating protein dynamics and protein-protein interactions using computer modeling and simulations. [Thesis]. Hong Kong University of Science and Technology; 2017. Available from: https://doi.org/10.14711/thesis-991012536069503412 ; http://repository.ust.hk/ir/bitstream/1783.1-88414/1/th_redirect.html

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of California – Berkeley

3. Bolin, Eric. Characterizing rare and transient conformations of proteins using amide hydrogen exchange and thiol exchange.

Degree: Biophysics, 2018, University of California – Berkeley

URL: http://www.escholarship.org/uc/item/1cd158xw

► The dynamic nature of proteins is often an underappreciated aspect of biology necessary for understanding protein function and turnover in the cell. This is in… (more)

▼ The dynamic nature of proteins is often an underappreciated aspect of biology necessary for understanding protein function and turnover in the cell. This is in part because within the multitude of states that a protein occupies throughout its lifetime, at most a few are significantly populated and have long enough lifetimes to study using traditional structural biology methods. In this thesis, I develop and explore experimental methods (amide hydrogen-deuterium exchange and cysteine labeling) to selectively label and characterize these rare and transient conformations methods. Specifically, I used cysteine labeling as a means to validate computational predictions of rare conformational fluctuations that expose potential drug-binding sites, I used pulse-labeling amide hydrogen exchange coupled with mass spectrometry detection to identify intermediates formed during protein folding and developed new data analysis procedures for analyzing hydrogen exchange rates measured determined by mass spectrometry on proteolytic fragments. The first project used thiol labeling rates to validate computational predictions of cryptic binding sites. Analysis of millisecond-long molecular dynamics (MD) simulations of β-lactamase uncovered several potential conformational fluctuations that expose hidden, or cryptic binding pockets. Targeting these rare conformations presents a potential avenue for drug development. I validated the existence of these pockets by introducing cysteine residues in select positions and characterizing their accessibility to chemical modifications. In addition to validating the existence of these fluctuations, modification of cysteines at these sites modulates activity allosterically.In the second project, I used pulsed labeling hydrogen exchange to follow the folding pathway of a protein family over evolutionary time (>3 billion years). I determined the conformations populated during folding (folding intermediates) for a family of RNase H proteins, including two extant and seven ancestral proteins. Each of these proteins was shown to populate a similar folding intermediate prior to the rate-limiting step in folding; however, the details of the steps leading up to this intermediate varied. We further showed that we can alter these early folding steps for a given protein using rationally designed mutations.The third project compared and characterized the refolding and co-translational folding pathway of the protein HaloTag. We found that HaloTag aggregates during refolding but not during cotranslational folding, and it adopts at least one intermediate during refolding that is suppressed during cotranslational folding.Finally, in the fourth project I developed a modification of a recently published approach for analyzing data from mass spectrometry-based detection of hydrogen exchange. This modification allows me to obtain multiple protection factors per peptide monitored and obtain a quantitative measurement of the free energy of hydrogen exchange in different regions of the protein.

Subjects/Keywords: Biophysics; Hydrogen Exchange; Protein Dynamics; Protein Folding

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APA (6^th Edition):

Bolin, E. (2018). Characterizing rare and transient conformations of proteins using amide hydrogen exchange and thiol exchange. (Thesis). University of California – Berkeley. Retrieved from http://www.escholarship.org/uc/item/1cd158xw

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Bolin, Eric. “Characterizing rare and transient conformations of proteins using amide hydrogen exchange and thiol exchange.” 2018. Thesis, University of California – Berkeley. Accessed August 24, 2019. http://www.escholarship.org/uc/item/1cd158xw.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Bolin, Eric. “Characterizing rare and transient conformations of proteins using amide hydrogen exchange and thiol exchange.” 2018. Web. 24 Aug 2019.

Vancouver:

Bolin E. Characterizing rare and transient conformations of proteins using amide hydrogen exchange and thiol exchange. [Internet] [Thesis]. University of California – Berkeley; 2018. [cited 2019 Aug 24]. Available from: http://www.escholarship.org/uc/item/1cd158xw.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Bolin E. Characterizing rare and transient conformations of proteins using amide hydrogen exchange and thiol exchange. [Thesis]. University of California – Berkeley; 2018. Available from: http://www.escholarship.org/uc/item/1cd158xw

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

4. Nakagawa, Hiroshi. Neutron incoherent scattering studies on protein dynamics : タンパク質動力学の中性子非干渉性散乱による研究; タンパクシツドウリキガクノチュウセイシヒカンショウセイサンランニヨルケンキュウ.

Degree: Nara Institute of Science and Technology / 奈良先端科学技術大学院大学

URL: http://hdl.handle.net/10061/4011

Subjects/Keywords: Protein dynamics

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APA (6^th Edition):

Nakagawa, H. (n.d.). Neutron incoherent scattering studies on protein dynamics : タンパク質動力学の中性子非干渉性散乱による研究; タンパクシツドウリキガクノチュウセイシヒカンショウセイサンランニヨルケンキュウ. (Thesis). Nara Institute of Science and Technology / 奈良先端科学技術大学院大学. Retrieved from http://hdl.handle.net/10061/4011

Note: this citation may be lacking information needed for this citation format:
No year of publication.
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Nakagawa, Hiroshi. “Neutron incoherent scattering studies on protein dynamics : タンパク質動力学の中性子非干渉性散乱による研究; タンパクシツドウリキガクノチュウセイシヒカンショウセイサンランニヨルケンキュウ.” Thesis, Nara Institute of Science and Technology / 奈良先端科学技術大学院大学. Accessed August 24, 2019. http://hdl.handle.net/10061/4011.

Note: this citation may be lacking information needed for this citation format:
No year of publication.
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Nakagawa, Hiroshi. “Neutron incoherent scattering studies on protein dynamics : タンパク質動力学の中性子非干渉性散乱による研究; タンパクシツドウリキガクノチュウセイシヒカンショウセイサンランニヨルケンキュウ.” Web. 24 Aug 2019.

Note: this citation may be lacking information needed for this citation format:
No year of publication.

Vancouver:

Nakagawa H. Neutron incoherent scattering studies on protein dynamics : タンパク質動力学の中性子非干渉性散乱による研究; タンパクシツドウリキガクノチュウセイシヒカンショウセイサンランニヨルケンキュウ. [Internet] [Thesis]. Nara Institute of Science and Technology / 奈良先端科学技術大学院大学; [cited 2019 Aug 24]. Available from: http://hdl.handle.net/10061/4011.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
No year of publication.

Council of Science Editors:

Nakagawa H. Neutron incoherent scattering studies on protein dynamics : タンパク質動力学の中性子非干渉性散乱による研究; タンパクシツドウリキガクノチュウセイシヒカンショウセイサンランニヨルケンキュウ. [Thesis]. Nara Institute of Science and Technology / 奈良先端科学技術大学院大学; Available from: http://hdl.handle.net/10061/4011

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
No year of publication.

University of Tennessee – Knoxville

5. Bernal Gomez, Ana Virginia. Conformational Dynamics of Cytochrome P450cam Upon Ligand Binding.

Degree: MS, Biochemistry and Cellular and Molecular Biology, 2015, University of Tennessee – Knoxville

URL: https://trace.tennessee.edu/utk_gradthes/3440

► Cytochrome P450s are a superfamily of metalloenzymes that are responsible for the monooxygenation of their hydrophobic substrates. P450’s retain the same general structural scaffold,… (more)

Subjects/Keywords: protein; dynamics; cytochrome; Biochemistry

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APA (6^th Edition):

Bernal Gomez, A. V. (2015). Conformational Dynamics of Cytochrome P450cam Upon Ligand Binding. (Thesis). University of Tennessee – Knoxville. Retrieved from https://trace.tennessee.edu/utk_gradthes/3440

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Bernal Gomez, Ana Virginia. “Conformational Dynamics of Cytochrome P450cam Upon Ligand Binding.” 2015. Thesis, University of Tennessee – Knoxville. Accessed August 24, 2019. https://trace.tennessee.edu/utk_gradthes/3440.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Bernal Gomez, Ana Virginia. “Conformational Dynamics of Cytochrome P450cam Upon Ligand Binding.” 2015. Web. 24 Aug 2019.

Vancouver:

Bernal Gomez AV. Conformational Dynamics of Cytochrome P450cam Upon Ligand Binding. [Internet] [Thesis]. University of Tennessee – Knoxville; 2015. [cited 2019 Aug 24]. Available from: https://trace.tennessee.edu/utk_gradthes/3440.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Bernal Gomez AV. Conformational Dynamics of Cytochrome P450cam Upon Ligand Binding. [Thesis]. University of Tennessee – Knoxville; 2015. Available from: https://trace.tennessee.edu/utk_gradthes/3440

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of Otago

6. Campbell, Eugene. Comparison of FRET probes of conformational changes in DnaK and Hsc70 .

Degree: University of Otago

URL: http://hdl.handle.net/10523/8526

► Hsp70s are one of the most well conserved protein families known, yet little of their in vivo activity is understood and experimental resources required to… (more)

▼ Hsp70s are one of the most well conserved protein families known, yet little of their in vivo activity is understood and experimental resources required to investigate their activity. All Hsp70s are made up of two highly conserved functional domains joined by a flexible linker, the nucleotide binding domain and the substrate binding domain. The Hsp70 proteins undergo a conformational in their peptide binding and release cycle, with conformation of the protein determined by the nucleotide bound in the nucleotide binding domain. This study compared the two most wildly studied Hsp70 proteins, DnaK and the human Hsc70, HSPA8. Hsc70 is a constitutively expressed member of the Hsp70 family which has many roles within the cell, assisting with folding of nascent polypeptides, targeting proteins for degradation and translocating proteins to the endoplasmic reticulum. Both proteins were purified from bacterial expression systems and the purification of Hsc70 was improved by the addition of an additional isocratic step during ion exchange chromatography. Efficiency of labelling with fluorescent dyes was improved and the activity cycle of DnaK and Hsc70 directly compared. Of the eight variants tested only two, DnaK variant C16S/K321C/E430C and Hsc70 variant E318C/T427C/C574S/C603S showed changes in FRET efficiency in response to different nucleotides. In order to validate these variants as suitable models and to probe why other variants showed no changes in FRET efficiency, proteins were analysed for their protein refolding activity. An improved luciferase refolding assay was developed to analyse the rate of protein refolding for each of the Hsc70 and DnaK variants. All of the variants for both DnaK and Hsc70 retained protein refolding activity, however most were less efficient than the wild type protein, showing between 20 to 100% of the wild type proteins activity. This study identified Hsc70 variant E318C/T427C/C574S/C603S as a suitable candidate for future in vivo fluorescence assay of Hsc70 function. Advisors/Committee Members: Wilbanks, Sigurd (advisor).

Subjects/Keywords: Protein; dynamics

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APA (6^th Edition):

Campbell, E. (n.d.). Comparison of FRET probes of conformational changes in DnaK and Hsc70 . (Masters Thesis). University of Otago. Retrieved from http://hdl.handle.net/10523/8526

Note: this citation may be lacking information needed for this citation format:
No year of publication.

Chicago Manual of Style (16^th Edition):

Campbell, Eugene. “Comparison of FRET probes of conformational changes in DnaK and Hsc70 .” Masters Thesis, University of Otago. Accessed August 24, 2019. http://hdl.handle.net/10523/8526.

Note: this citation may be lacking information needed for this citation format:
No year of publication.

MLA Handbook (7^th Edition):

Campbell, Eugene. “Comparison of FRET probes of conformational changes in DnaK and Hsc70 .” Web. 24 Aug 2019.

Note: this citation may be lacking information needed for this citation format:
No year of publication.

Vancouver:

Campbell E. Comparison of FRET probes of conformational changes in DnaK and Hsc70 . [Internet] [Masters thesis]. University of Otago; [cited 2019 Aug 24]. Available from: http://hdl.handle.net/10523/8526.

Note: this citation may be lacking information needed for this citation format:
No year of publication.

Council of Science Editors:

Campbell E. Comparison of FRET probes of conformational changes in DnaK and Hsc70 . [Masters Thesis]. University of Otago; Available from: http://hdl.handle.net/10523/8526

Note: this citation may be lacking information needed for this citation format:
No year of publication.

Northeastern University

7. Yang, Huan. Dissecting the structural and energetic factors that govern biological dynamics.

Degree: PhD, Department of Physics, 2018, Northeastern University

URL: http://hdl.handle.net/2047/D20285300

► Energy landscape theory has provided a framework for understanding the dynamics of biomolecules. The successes of energy landscape approaches to understand folding, combined with countless… (more)

▼ Energy landscape theory has provided a framework for understanding the dynamics of biomolecules. The successes of energy landscape approaches to understand folding, combined with countless advances in structural biology techniques, has inspired the field to extend these techniques to study large molecular machines, e.g. the ribosome. The ribosome is the sole producer of protein in the cell, where protein synthesis is accomplished through the elongation cycle. In this thesis, we focus on a substep of the elongation cycles, tRNA accommodation. Accommodation involves a large-scale ~100Å conformational change in aminoacyl-tRNA (aa-tRNA), where the molecule transits from the A/T to A/A configuration. Chapter 2 describes how we used an all-atom structure-based model to simulate the aa-tRNA accommodation process. We quantified the free-energy landscape of accommodation as well as elucidated the interplay between movement of the L11 stalk and tRNA molecule. We found that L11 stalk mobility can impact the kinetics of the aa-tRNA rearrangement. In addition, we showed that the steric effect imposed by the L11 stalk and EF-Tu can additively accelerate the aa-tRNA transition. Chapter 3 describes how we applied a coarse-grained structure-based model to study domain rearrangements in EF-Tu. Specifically, we studied large-scale domain separation and domain rotation in EF-Tu. Our results indicate that EF-Tu adopts a wide range of extended configurations during the transition from the pre to post conformation. Finally, in order to connect the energy landscapes calculated from simulation with experimental rates, in chapter 4 we provided a theoretical framework for understanding the origins of the coordinate-dependent diffusion of tRNA inside of the ribosome. This involves the use of many short timescale explicit-solvent simulations, initialized from various points along the accommodation process. Combined with the free-energy profile obtained from simplified model, we estimated the speed limit of aa-tRNA accommodation to be 2500s-1 and found that the detailed energetic interactions between tRNA and the ribosome can lead to order-of-magnitude oscillations in the effective diffusion coefficient. This data set allows us to estimate the effective timescales for simplified models, which provides a theoretical framework for connecting simulated timescales with experimental observables.

Subjects/Keywords: molecular dynamics; protein synthesis; ribosome

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APA (6^th Edition):

Yang, H. (2018). Dissecting the structural and energetic factors that govern biological dynamics. (Doctoral Dissertation). Northeastern University. Retrieved from http://hdl.handle.net/2047/D20285300

Chicago Manual of Style (16^th Edition):

Yang, Huan. “Dissecting the structural and energetic factors that govern biological dynamics.” 2018. Doctoral Dissertation, Northeastern University. Accessed August 24, 2019. http://hdl.handle.net/2047/D20285300.

MLA Handbook (7^th Edition):

Yang, Huan. “Dissecting the structural and energetic factors that govern biological dynamics.” 2018. Web. 24 Aug 2019.

Vancouver:

Yang H. Dissecting the structural and energetic factors that govern biological dynamics. [Internet] [Doctoral dissertation]. Northeastern University; 2018. [cited 2019 Aug 24]. Available from: http://hdl.handle.net/2047/D20285300.

Council of Science Editors:

Yang H. Dissecting the structural and energetic factors that govern biological dynamics. [Doctoral Dissertation]. Northeastern University; 2018. Available from: http://hdl.handle.net/2047/D20285300

University of Pennsylvania

8. O'brien, Evan. Structure, Function & Dynamics At The Membrane.

Degree: 2018, University of Pennsylvania

URL: https://repository.upenn.edu/edissertations/3165

► The biological membrane is necessary for maintaining cellular identity, yet must also allow for interaction with the extracellular environment in order to respond to stimuli.… (more)

▼ The biological membrane is necessary for maintaining cellular identity, yet must also allow for interaction with the extracellular environment in order to respond to stimuli. Proteins that are directly embedded in the membrane or that interact more peripherally are responsible for these extracellular signaling events, which lie at the heart of cell communication. The first major goal of this work was to interrogate the peripheral interaction of cytochrome c and the mitochondrial lipid cardiolipin at atomic resolution using solution nuclear magnetic resonance (NMR) techniques; this interaction is key to promoting apoptosis. After demonstrating that the protein was correctly folded in the reverse micelle solution used as a membrane mimetic, cardiolipin was introduced to confirm two previously predicted sites of interaction as well as to identify and propose a novel third site. Next, NMR-derived methyl side chain order parameters have been shown to be important in the thermodynamics of intermolecular interactions. Molecular simulation has become routine in investigations of protein dynamics with atomic-level information, yet their accuracy in replicating experimental dynamics measurements is unknown. Using a variety of standard “force-fields”, it becomes apparent that both common implementations perform comparably, yet outside of the model ubiquitin system, much progress remains in this area. Simulations were then used to interrogate the role of backbone motions in protein thermodynamics. Finally, though we now know much about the role of methyl dynamics in protein conformational entropy, this view has been attained solely with soluble protein systems; the dynamic behavior of membrane proteins remains to be elucidated. Utilizing a newly designed labeling technique for producing deuterated, appropriately methyl-labeled samples, we collected the first quantitative side chain dynamics experiments on several large, integral membrane protein systems. These experiments revealed that membrane proteins apparently contain massive wells of residual conformational entropy, manifested in the extremely dynamic average behavior of the side chain methyl groups. This extraordinary average behavior is the result of the emergence of a previously unobserved “hyper-dynamic” band of methyl groups that explore extensive amounts of rotameric space. In contrast, a series of structural waters and buried polar residues are very rigid by simulation and appear necessary for maintaining a single tertiary structure.

Subjects/Keywords: apoptosis; membrane; molecular dynamics; NMR; protein dynamics; protein structure; Biochemistry; Biophysics

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APA (6^th Edition):

O'brien, E. (2018). Structure, Function & Dynamics At The Membrane. (Thesis). University of Pennsylvania. Retrieved from https://repository.upenn.edu/edissertations/3165

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

O'brien, Evan. “Structure, Function & Dynamics At The Membrane.” 2018. Thesis, University of Pennsylvania. Accessed August 24, 2019. https://repository.upenn.edu/edissertations/3165.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

O'brien, Evan. “Structure, Function & Dynamics At The Membrane.” 2018. Web. 24 Aug 2019.

Vancouver:

O'brien E. Structure, Function & Dynamics At The Membrane. [Internet] [Thesis]. University of Pennsylvania; 2018. [cited 2019 Aug 24]. Available from: https://repository.upenn.edu/edissertations/3165.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

O'brien E. Structure, Function & Dynamics At The Membrane. [Thesis]. University of Pennsylvania; 2018. Available from: https://repository.upenn.edu/edissertations/3165

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of Kansas

9. Rui, Huan. Computational Studies of Protein Structure, Dynamics, and Function in Native-like Environments.

Degree: PhD, Biochemistry & Molecular Biology, 2013, University of Kansas

URL: http://hdl.handle.net/1808/14217

► Proteins are among the four unique organic constituents of cells. They are responsible for a variety of important cell functions ranging from providing structural support… (more)

▼ Proteins are among the four unique organic constituents of cells. They are responsible for a variety of important cell functions ranging from providing structural support to catalyzing biological reactions. They vary in shape, dynamic behavior, and localization. All of these together determine the specificity in their functions, but the question is how. The ultimate goal of the research conducted in this thesis is to answer this question. Two types of proteins are of particular interest. They include transmembrane proteins and protein assemblies. Using computer simulations with available experimental data to validate the simulation results, the research described here aims to reveal the structure and dynamics of proteins in their native-like environment and the indication on the mechanism of their functions. The first part of the thesis focuses on studying the structure and functions of transmembrane proteins. These proteins are consisted of transmembrane α-helices or β-strands, and each of the secondary structure elements adopts a unique orientation in the membrane following its local interactions. The structure of the entire protein is a collection of the orientations of these elements and their relative positions with respect to one another. These two basic aspects of membrane protein structure are studied in Chapter II and III. In Chapter II, efforts are given to determine the favorable orientation of a β-hairpin peptide, protegrin-1, in different lipid bilayers. The orientational preference results from the interplay between the protein and the surrounding lipid molecules. Chapter III is centered on revealing the structure and dynamics of caveolin-1 in DMPC bilayers. Caveolin-1 forms a re-entrant helix-turn-helix structure with two α-helices embedded in the membrane bilayer. The study shows that caveolin-1 monomer is rather dynamic and maintains its inserted conformation via both specific and non-specific protein-lipid interactions. To investigate the structural and dynamic impact on the function of a membrane protein, molecular dynamics simulations of the voltage-dependent anion channel are performed and the results are presented in Chapter IV. It is found in this chapter that the electrostatic interactions between charged residues on the channel wall facing the lumen are responsible for retarding the cation current, therefore giving the channel its anion selectivity. The second category of protein that is of interest in this thesis is the assembled protein complex, especially the ones that are highly symmetric. Actually, many membrane proteins belong to this category as well, but the study presented here in Chapter V involves simulations performed on a soluble protein complex, bacterioferritin B from Pseudomonas Aeruginosa. It is revealed by the simulations that the dynamic behavior of the protein is magnified by the symmetry and is tightly associated to its function. Advisors/Committee Members: Im, Wonpil (advisor), Deeds, Eric (cmtemember), Karanicolas, John (cmtemember), Rivera, Mario (cmtemember), Vakser, Ilya (cmtemember).

Subjects/Keywords: Bioinformatics; Biophysics; Biochemistry; Membrane bilayers; Membrane protein; Molecular dynamics simulations; Protein assembly; Protein dynamics

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Rui, H. (2013). Computational Studies of Protein Structure, Dynamics, and Function in Native-like Environments. (Doctoral Dissertation). University of Kansas. Retrieved from http://hdl.handle.net/1808/14217

Chicago Manual of Style (16^th Edition):

Rui, Huan. “Computational Studies of Protein Structure, Dynamics, and Function in Native-like Environments.” 2013. Doctoral Dissertation, University of Kansas. Accessed August 24, 2019. http://hdl.handle.net/1808/14217.

MLA Handbook (7^th Edition):

Rui, Huan. “Computational Studies of Protein Structure, Dynamics, and Function in Native-like Environments.” 2013. Web. 24 Aug 2019.

Vancouver:

Rui H. Computational Studies of Protein Structure, Dynamics, and Function in Native-like Environments. [Internet] [Doctoral dissertation]. University of Kansas; 2013. [cited 2019 Aug 24]. Available from: http://hdl.handle.net/1808/14217.

Council of Science Editors:

Rui H. Computational Studies of Protein Structure, Dynamics, and Function in Native-like Environments. [Doctoral Dissertation]. University of Kansas; 2013. Available from: http://hdl.handle.net/1808/14217

Indian Institute of Science

10. Katagi, Gurunath M. Analysis of Molecular Dynamics Trajectories of Proteins Performed using Different Forcefields and Identifiction of Mobile Segments.

Degree: 2013, Indian Institute of Science

URL: http://etd.iisc.ernet.in/2005/3327 ; http://etd.iisc.ernet.in/abstracts/4191/G25705-Abs.pdf

► The selection of the forcefield is a crucial issue in any MD related work and there is no clear indication as to which of the… (more)

▼ The selection of the forcefield is a crucial issue in any MD related work and there is no clear indication as to which of the many available forcefields is the best for protein analysis. Many recent literature surveys indicate that MD work may be hindered by two limitations, namely conformational sampling and forcefields used (inaccuracies in the potential energy function may bias the simulation toward incorrect conformations). However, the advances in computing infrastructures, theoretical and computing aspects of MD have paved the way to carry out a sampling on a sufficiently longtime scale, putting a need for the accuracies in the forcefield. Because there are established differences in MD results when using forcefields, we have sought to ask how we could assess common mobility segments from a protein by analysis of trajectories using three forcefields in a similar environment. This is important because, disparate fluctuations appear to be more at flexible regions compared to stiff regions; in particular, flexible regions are more relevant to functional activities of the protein molecule. Therefore, we have tried to assess the similarity in the dynamics using three well-known forcefields ENCAD, CHARMM27 and AMBERFF99SB for 61 monomeric proteins and identify the properties of dynamic residues, which may be important for function. The comparison of popular forcefields with different parameterization philosophy may give hints to improve some of the currently existing agnostics in forcefields and characterization of mobile regions based on dynamics of proteins with diverse folds. These may also give some signature on the proteins at the level of dynamics in relation to function, which can be used in protein engineering studies. Nanosecond level MD simulation(30ns) on 61 monomeric proteins were carried out using CHARMM and AMBER forcefields and the trajectories with ENCAD forcefield obtained from Dynameomics database. The trajectories were first analyzed to check whether structural and dynamic properties from the three forcefields similar choosing few parameters in each case. The gross dynamic properties calculated (root mean square deviation (RMSD), TM-score derived RMSD, radius of gyration and accessible surface area) indicated similarity in many proteins. Flexibility index analysis on 17 proteins, which showed a notable difference in the flexibility, indicated that tertiary interactions (fraction of nonnative stable hydrogen bonds and salt bridges) might be responsible for the difference in the flexibility index. The normalized subspace overlap and shape overlap score taken based on the covariance matrices derived from trajectories indicated that majority of the proteins show a range between 0.3-0.5 indicating that the first principal components from these proteins in different combinations may not match well. These results indicate that although dynamic properties in general are similar in many proteins. However, flexibility index and normalized subspace overlap score indicate that subspaces on the first… Advisors/Committee Members: Pal, Debnath.

Subjects/Keywords: Protein Structures; Protein Dynamics; Protein Functions; Proteins - Analysis; Proteins - Molecular Dynamics Simulations; Protein Flexibility; Protein Simulation Trajectories; Forcefields - Protein Analysis; Protein Structure - Computation; Molecular Dynamics Simulations; MD Simulations; Biochemistry

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Katagi, G. M. (2013). Analysis of Molecular Dynamics Trajectories of Proteins Performed using Different Forcefields and Identifiction of Mobile Segments. (Thesis). Indian Institute of Science. Retrieved from http://etd.iisc.ernet.in/2005/3327 ; http://etd.iisc.ernet.in/abstracts/4191/G25705-Abs.pdf

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Katagi, Gurunath M. “Analysis of Molecular Dynamics Trajectories of Proteins Performed using Different Forcefields and Identifiction of Mobile Segments.” 2013. Thesis, Indian Institute of Science. Accessed August 24, 2019. http://etd.iisc.ernet.in/2005/3327 ; http://etd.iisc.ernet.in/abstracts/4191/G25705-Abs.pdf.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Katagi, Gurunath M. “Analysis of Molecular Dynamics Trajectories of Proteins Performed using Different Forcefields and Identifiction of Mobile Segments.” 2013. Web. 24 Aug 2019.

Vancouver:

Katagi GM. Analysis of Molecular Dynamics Trajectories of Proteins Performed using Different Forcefields and Identifiction of Mobile Segments. [Internet] [Thesis]. Indian Institute of Science; 2013. [cited 2019 Aug 24]. Available from: http://etd.iisc.ernet.in/2005/3327 ; http://etd.iisc.ernet.in/abstracts/4191/G25705-Abs.pdf.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Katagi GM. Analysis of Molecular Dynamics Trajectories of Proteins Performed using Different Forcefields and Identifiction of Mobile Segments. [Thesis]. Indian Institute of Science; 2013. Available from: http://etd.iisc.ernet.in/2005/3327 ; http://etd.iisc.ernet.in/abstracts/4191/G25705-Abs.pdf

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Indian Institute of Science

11. Adkar, Bharat V. Computational And Experimental Studies On Protein Structure, Stability And Dynamics.

Degree: 2011, Indian Institute of Science

URL: http://hdl.handle.net/2005/2369

► The work in this thesis focuses on the study of three main aspects of proteins, viz, Protein structure, stability, and dynamics. Chapter 1 is a… (more)

▼ The work in this thesis focuses on the study of three main aspects of proteins, viz, Protein structure, stability, and dynamics. Chapter 1 is a general introduction to the topics studied in this thesis. Chapter 2 deals with the first aspect, i.e., protein structure in which we describe an approach to use saturation mutagenesis phenotypes to guide protein structure prediction. Chapters 3 and 4 discuss how to increase protein stability using surface electrostatics, and Chapter 5 details a method to predict whether a proline substitution in a given protein would be stabilizing or destabilizing. Hence, Chapters 3-5 can be associated with the second aspect, i.e., protein stability. The third aspect, namely protein dynamics, is dealt with in Chapters 6 and 7 which study conformational dynamics of adenylate kinase. Protein structure prediction is a difficult problem with two major bottlenecks, namely, generation of accurate models and the selection of the most appropriate models from a large pool of decoys. In Chapter 2, the problem of model discrimination is addressed using mutant phenotype information derived from saturation mutagenesis library. A library of ~1500 single-site mutants of the E. coli toxin CcdB (Controller of Cell Division or Death B) has been previously constructed in our lab. The pooled library was characterized in terms of individual mutant phenotypes at various expression levels which were derived from the relative populations of mutants at each expression level. The relative populations of mutants were estimated using deep sequencing. Mutational tolerances were derived from the phenotypic data and were used to define an empirical parameter which correlated with a structural parameter, residue depth. We further studied how this new parameter can be used for model discrimination. Increasing protein stability in a rational way is a challenging problem and has been addressed by various approaches. One of the most commonly used approaches is optimization of protein core residues. Recently, optimization of protein surface electrostatics has been shown to be a useful approach for increasing stability of proteins. In Chapter 3, from analyses of a dataset of ~1750 non-homologues proteins, we show that proteins having a pI away from physiological pH, possess a significant fraction of unfavorably placed charged amino acids on their surface. One way to increase protein stability in such cases might be to alter these surface charges. This hypothesis was validated experimentally by making charge reversal mutations at putative unfavorable positions on the surface of maltose binding protein, MBP. The observed stabilization can potentially be increased by combining multiple individually stabilizing mutations. Different combinations of such mutations were made and tested in Chapter 4 to decide which mutants can be combined to achieve net stabilization. Ideas were tested through systematic experimentation which involved generation of two-site, three-site, and four-site mutations. A maximum increase in melting… Advisors/Committee Members: Varadarajan, Raghavan, Bagchi, Biman.

Subjects/Keywords: Proteins; Protein Structure; Protein Stability; Protein Dynamics; Protein Surface Electrostatics; Adenylate Kinase; Proline Mutations; Biochemistry

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Adkar, B. V. (2011). Computational And Experimental Studies On Protein Structure, Stability And Dynamics. (Thesis). Indian Institute of Science. Retrieved from http://hdl.handle.net/2005/2369

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Adkar, Bharat V. “Computational And Experimental Studies On Protein Structure, Stability And Dynamics.” 2011. Thesis, Indian Institute of Science. Accessed August 24, 2019. http://hdl.handle.net/2005/2369.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Adkar, Bharat V. “Computational And Experimental Studies On Protein Structure, Stability And Dynamics.” 2011. Web. 24 Aug 2019.

Vancouver:

Adkar BV. Computational And Experimental Studies On Protein Structure, Stability And Dynamics. [Internet] [Thesis]. Indian Institute of Science; 2011. [cited 2019 Aug 24]. Available from: http://hdl.handle.net/2005/2369.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Adkar BV. Computational And Experimental Studies On Protein Structure, Stability And Dynamics. [Thesis]. Indian Institute of Science; 2011. Available from: http://hdl.handle.net/2005/2369

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Indian Institute of Science

12. Adkar, Bharat V. Computational And Experimental Studies On Protein Structure, Stability And Dynamics.

Degree: 2011, Indian Institute of Science

URL: http://etd.iisc.ernet.in/handle/2005/2369 ; http://etd.ncsi.iisc.ernet.in/abstracts/3049/G25086-Abs.pdf

► The work in this thesis focuses on the study of three main aspects of proteins, viz, Protein structure, stability, and dynamics. Chapter 1 is a… (more)

▼ The work in this thesis focuses on the study of three main aspects of proteins, viz, Protein structure, stability, and dynamics. Chapter 1 is a general introduction to the topics studied in this thesis. Chapter 2 deals with the first aspect, i.e., protein structure in which we describe an approach to use saturation mutagenesis phenotypes to guide protein structure prediction. Chapters 3 and 4 discuss how to increase protein stability using surface electrostatics, and Chapter 5 details a method to predict whether a proline substitution in a given protein would be stabilizing or destabilizing. Hence, Chapters 3-5 can be associated with the second aspect, i.e., protein stability. The third aspect, namely protein dynamics, is dealt with in Chapters 6 and 7 which study conformational dynamics of adenylate kinase. Protein structure prediction is a difficult problem with two major bottlenecks, namely, generation of accurate models and the selection of the most appropriate models from a large pool of decoys. In Chapter 2, the problem of model discrimination is addressed using mutant phenotype information derived from saturation mutagenesis library. A library of ~1500 single-site mutants of the E. coli toxin CcdB (Controller of Cell Division or Death B) has been previously constructed in our lab. The pooled library was characterized in terms of individual mutant phenotypes at various expression levels which were derived from the relative populations of mutants at each expression level. The relative populations of mutants were estimated using deep sequencing. Mutational tolerances were derived from the phenotypic data and were used to define an empirical parameter which correlated with a structural parameter, residue depth. We further studied how this new parameter can be used for model discrimination. Increasing protein stability in a rational way is a challenging problem and has been addressed by various approaches. One of the most commonly used approaches is optimization of protein core residues. Recently, optimization of protein surface electrostatics has been shown to be a useful approach for increasing stability of proteins. In Chapter 3, from analyses of a dataset of ~1750 non-homologues proteins, we show that proteins having a pI away from physiological pH, possess a significant fraction of unfavorably placed charged amino acids on their surface. One way to increase protein stability in such cases might be to alter these surface charges. This hypothesis was validated experimentally by making charge reversal mutations at putative unfavorable positions on the surface of maltose binding protein, MBP. The observed stabilization can potentially be increased by combining multiple individually stabilizing mutations. Different combinations of such mutations were made and tested in Chapter 4 to decide which mutants can be combined to achieve net stabilization. Ideas were tested through systematic experimentation which involved generation of two-site, three-site, and four-site mutations. A maximum increase in melting… Advisors/Committee Members: Varadarajan, Raghavan, Bagchi, Biman.

Subjects/Keywords: Proteins; Protein Structure; Protein Stability; Protein Dynamics; Protein Surface Electrostatics; Adenylate Kinase; Proline Mutations; Biochemistry

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Adkar, B. V. (2011). Computational And Experimental Studies On Protein Structure, Stability And Dynamics. (Thesis). Indian Institute of Science. Retrieved from http://etd.iisc.ernet.in/handle/2005/2369 ; http://etd.ncsi.iisc.ernet.in/abstracts/3049/G25086-Abs.pdf

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Adkar, Bharat V. “Computational And Experimental Studies On Protein Structure, Stability And Dynamics.” 2011. Thesis, Indian Institute of Science. Accessed August 24, 2019. http://etd.iisc.ernet.in/handle/2005/2369 ; http://etd.ncsi.iisc.ernet.in/abstracts/3049/G25086-Abs.pdf.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Adkar, Bharat V. “Computational And Experimental Studies On Protein Structure, Stability And Dynamics.” 2011. Web. 24 Aug 2019.

Vancouver:

Adkar BV. Computational And Experimental Studies On Protein Structure, Stability And Dynamics. [Internet] [Thesis]. Indian Institute of Science; 2011. [cited 2019 Aug 24]. Available from: http://etd.iisc.ernet.in/handle/2005/2369 ; http://etd.ncsi.iisc.ernet.in/abstracts/3049/G25086-Abs.pdf.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Adkar BV. Computational And Experimental Studies On Protein Structure, Stability And Dynamics. [Thesis]. Indian Institute of Science; 2011. Available from: http://etd.iisc.ernet.in/handle/2005/2369 ; http://etd.ncsi.iisc.ernet.in/abstracts/3049/G25086-Abs.pdf

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of Ottawa

13. Davey, James A. Multistate Computational Protein Design: Theories, Methods, and Applications .

Degree: 2016, University of Ottawa

URL: http://hdl.handle.net/10393/35541

► Traditional computational protein design (CPD) calculations model sequence perturbations and evaluate their stabilities using a single fixed protein backbone template in an approach referred to… (more)

Subjects/Keywords: computational protein design; multistate design; protein engineering; molecular modeling; substrate multispecificity; protein stability; protein dynamics

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Davey, J. A. (2016). Multistate Computational Protein Design: Theories, Methods, and Applications . (Thesis). University of Ottawa. Retrieved from http://hdl.handle.net/10393/35541

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Davey, James A. “Multistate Computational Protein Design: Theories, Methods, and Applications .” 2016. Thesis, University of Ottawa. Accessed August 24, 2019. http://hdl.handle.net/10393/35541.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Davey, James A. “Multistate Computational Protein Design: Theories, Methods, and Applications .” 2016. Web. 24 Aug 2019.

Vancouver:

Davey JA. Multistate Computational Protein Design: Theories, Methods, and Applications . [Internet] [Thesis]. University of Ottawa; 2016. [cited 2019 Aug 24]. Available from: http://hdl.handle.net/10393/35541.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Davey JA. Multistate Computational Protein Design: Theories, Methods, and Applications . [Thesis]. University of Ottawa; 2016. Available from: http://hdl.handle.net/10393/35541

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

The Ohio State University

14. Zhang, Luyuan. Ultrafast Protein Hydration Dynamics Probed by Intrinsic Tryptophan.

Degree: PhD, Chemical Physics, 2010, The Ohio State University

URL: http://rave.ohiolink.edu/etdc/view?acc_num=osu1276524825

► Elucidation of water-protein interactions and dynamics is essential to the understanding of protein structure, dynamics and function. In this dissertation, we describe a novel methodology… (more)

Subjects/Keywords: Biophysics; Protein hydration dynamics; tryptophan; correlation

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Zhang, L. (2010). Ultrafast Protein Hydration Dynamics Probed by Intrinsic Tryptophan. (Doctoral Dissertation). The Ohio State University. Retrieved from http://rave.ohiolink.edu/etdc/view?acc_num=osu1276524825

Chicago Manual of Style (16^th Edition):

Zhang, Luyuan. “Ultrafast Protein Hydration Dynamics Probed by Intrinsic Tryptophan.” 2010. Doctoral Dissertation, The Ohio State University. Accessed August 24, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=osu1276524825.

MLA Handbook (7^th Edition):

Zhang, Luyuan. “Ultrafast Protein Hydration Dynamics Probed by Intrinsic Tryptophan.” 2010. Web. 24 Aug 2019.

Vancouver:

Zhang L. Ultrafast Protein Hydration Dynamics Probed by Intrinsic Tryptophan. [Internet] [Doctoral dissertation]. The Ohio State University; 2010. [cited 2019 Aug 24]. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=osu1276524825.

Council of Science Editors:

Zhang L. Ultrafast Protein Hydration Dynamics Probed by Intrinsic Tryptophan. [Doctoral Dissertation]. The Ohio State University; 2010. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=osu1276524825

Case Western Reserve University

15. Seckler, James Malcolm. The Structural Dynamics of Human Immunodeficiency Virus Type I Reverse Transcriptase.

Degree: PhD, Physiology and Biophysics, 2011, Case Western Reserve University

URL: http://rave.ohiolink.edu/etdc/view?acc_num=case1298562809

► Human Immunodeficiency Virus Type 1 Reverse Transcriptase (RT) is the protein in HIV responsible for transcribing viral RNA into double stranded DNA, making it an… (more)

▼ Human Immunodeficiency Virus Type 1 Reverse Transcriptase (RT) is the protein in HIV responsible for transcribing viral RNA into double stranded DNA, making it an essential component in viral infectivity and the most popular target for anti-viral therapies for HIV. Over the years, a plethora of inhibitors for RT have been developed, and many of them are currently approved for clinical use. Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI) are small molecules that act as non-competitive, allosteric inhibitors of RT, binding in a binding pocket inside of the polymerase domain of RT and hampering enzymatic activity. Although this is a widely used class of viral inhibitor, the mechanism of inhibition is currently unknown. In addition to this, most current knowledge of RT is concentrated on the heterodimer, while little is known of the monomeric precursors to this structure. In this study we employ HXMS and SAXS to probe the solution structural dynamics and solution structure of RT heterodimer and monomers. We show that the p51 subunit does not form the stable core of the protein. Rather the core consists of the fingers and palm subdomains of both subunits. A ß-sheet that forms half of the NNRTI binding site undergoes slow cooperative unfolding, which is slowed by several orders of magnitude upon NNRTI binding. In addition to this, HXMS analysis reveals an allosteric network of regions that spans both subunits of the RT heterodimer. This network is thought to play a vital role in RT inhibition. The structural dynamics and solution structure of RT monomers were determined, revealing that the monomers were structured but more flexible in solution compared to the solution structure of the heterodimer. HXMS revealed that the monomers had nearly identical secondary structure, with the main difference being slow cooperative unfolding in the p66 thumb subdomain. SAXS revealed that both monomers exist in an ensemble of conformation. The polymerase domain of both monomers exists both in an open p66-like conformation, a closed p51-like conformation, and several unique conformations. This research lays the foundation for a novel method of drug screening and discovery. Advisors/Committee Members: Hopfer, Ulrich (Committee Chair), Wintrode, Patrick (Advisor).

Subjects/Keywords: Biophysics; HIV; reverse transcriptase; protein dynamics

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Seckler, J. M. (2011). The Structural Dynamics of Human Immunodeficiency Virus Type I Reverse Transcriptase. (Doctoral Dissertation). Case Western Reserve University. Retrieved from http://rave.ohiolink.edu/etdc/view?acc_num=case1298562809

Chicago Manual of Style (16^th Edition):

Seckler, James Malcolm. “The Structural Dynamics of Human Immunodeficiency Virus Type I Reverse Transcriptase.” 2011. Doctoral Dissertation, Case Western Reserve University. Accessed August 24, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=case1298562809.

MLA Handbook (7^th Edition):

Seckler, James Malcolm. “The Structural Dynamics of Human Immunodeficiency Virus Type I Reverse Transcriptase.” 2011. Web. 24 Aug 2019.

Vancouver:

Seckler JM. The Structural Dynamics of Human Immunodeficiency Virus Type I Reverse Transcriptase. [Internet] [Doctoral dissertation]. Case Western Reserve University; 2011. [cited 2019 Aug 24]. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=case1298562809.

Council of Science Editors:

Seckler JM. The Structural Dynamics of Human Immunodeficiency Virus Type I Reverse Transcriptase. [Doctoral Dissertation]. Case Western Reserve University; 2011. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=case1298562809

Louisiana State University

16. Rojas, Ana. A study of the elongation of fibrils of the Alzheimer's amyloid beta protein with a coarse-grained force field.

Degree: PhD, Physical Sciences and Mathematics, 2010, Louisiana State University

URL: etd-08162010-102550 ; https://digitalcommons.lsu.edu/gradschool_dissertations/351

► Alzheimer’s disease (AD) is a brain disorder named after the German psychiatrist Alois Alzheimer, who first described the disease in 1906. AD is a form… (more)

Subjects/Keywords: protein folding; misfolding disease; molecular dynamics; simulations

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Rojas, A. (2010). A study of the elongation of fibrils of the Alzheimer's amyloid beta protein with a coarse-grained force field. (Doctoral Dissertation). Louisiana State University. Retrieved from etd-08162010-102550 ; https://digitalcommons.lsu.edu/gradschool_dissertations/351

Chicago Manual of Style (16^th Edition):

Rojas, Ana. “A study of the elongation of fibrils of the Alzheimer's amyloid beta protein with a coarse-grained force field.” 2010. Doctoral Dissertation, Louisiana State University. Accessed August 24, 2019. etd-08162010-102550 ; https://digitalcommons.lsu.edu/gradschool_dissertations/351.

MLA Handbook (7^th Edition):

Rojas, Ana. “A study of the elongation of fibrils of the Alzheimer's amyloid beta protein with a coarse-grained force field.” 2010. Web. 24 Aug 2019.

Vancouver:

Rojas A. A study of the elongation of fibrils of the Alzheimer's amyloid beta protein with a coarse-grained force field. [Internet] [Doctoral dissertation]. Louisiana State University; 2010. [cited 2019 Aug 24]. Available from: etd-08162010-102550 ; https://digitalcommons.lsu.edu/gradschool_dissertations/351.

Council of Science Editors:

Rojas A. A study of the elongation of fibrils of the Alzheimer's amyloid beta protein with a coarse-grained force field. [Doctoral Dissertation]. Louisiana State University; 2010. Available from: etd-08162010-102550 ; https://digitalcommons.lsu.edu/gradschool_dissertations/351

University of Tennessee – Knoxville

17. Evangelista Falcón, Wilfredo. The Role of Protein Structural Ensembles in Thermostability and Ligand Binding.

Degree: 2017, University of Tennessee – Knoxville

URL: https://trace.tennessee.edu/utk_graddiss/4854

► The role of protein structural ensembles has been shown to be very important for different physical and chemical properties of proteins. The work presented in… (more)

▼ The role of protein structural ensembles has been shown to be very important for different physical and chemical properties of proteins. The work presented in this dissertation explores two of these properties:i) Thermostability, by characterizing, at three different temperatures, the dynamics of aminoglycoside nucleotidyltransferase 4’ (ANT). This homodimeric enzyme detoxifies antibiotics. It possess two known variants, D80Y and T130K, with higher melting temperatures than the wild type. These mutations, however, would cause changes in the distributions of conformations in the ensemble and, consequently, on the dynamics of the protein. To test this hypothesis, the wild type and variants were examined by using molecular dynamics simulations and the results were compared with previous experimental information in order to characterize the similarities and differences between the, so-called, thermophilic and thermostable variants of this enzyme.ii) Ligand binding: Since proteins are in general dynamic structures, it would be expected that the effectiveness of ligand binding varies as the protein’s conformation changes. One of the most targeted protein family in the field of drug discovery/design is the G-Protein Coupled Receptor (GPCR) family. Over 30% of approved drugs target this family of proteins. This project examines, via in silico experiments, the differences in ligand binding between different conformations of GPCRs. To this end, GPCR ligand structures, actual binding (actives) and non-binding (decoys) ligands, were obtained from public databases, and eight GPCRs structures were selected to generate 5,000 conformational states for each protein. Ensemble-based docking was performed on representative structures of these 5,000 conformers and on a subset of 3,000 conformers from each of the eight proteins. Decoys and statistical analysis were incorporated in the docking simulations to test whether the sampled protein conformations can bind active ligands in greater numbers than the random selection from the pool of active and decoys. The results show that some conformations bind more ligands than other conformations, random selection, or the crystal structure. Characterizing the entire ensemble of protein conformations can improve the number of bound active ligands identified computationally, compared to random selection of compounds or docking using only a single crystal structure.

Subjects/Keywords: Molecular Dynamics; Protein simulations; Docking; Thermostability

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APA (6^th Edition):

Evangelista Falcón, W. (2017). The Role of Protein Structural Ensembles in Thermostability and Ligand Binding. (Doctoral Dissertation). University of Tennessee – Knoxville. Retrieved from https://trace.tennessee.edu/utk_graddiss/4854

Chicago Manual of Style (16^th Edition):

Evangelista Falcón, Wilfredo. “The Role of Protein Structural Ensembles in Thermostability and Ligand Binding.” 2017. Doctoral Dissertation, University of Tennessee – Knoxville. Accessed August 24, 2019. https://trace.tennessee.edu/utk_graddiss/4854.

MLA Handbook (7^th Edition):

Evangelista Falcón, Wilfredo. “The Role of Protein Structural Ensembles in Thermostability and Ligand Binding.” 2017. Web. 24 Aug 2019.

Vancouver:

Evangelista Falcón W. The Role of Protein Structural Ensembles in Thermostability and Ligand Binding. [Internet] [Doctoral dissertation]. University of Tennessee – Knoxville; 2017. [cited 2019 Aug 24]. Available from: https://trace.tennessee.edu/utk_graddiss/4854.

Council of Science Editors:

Evangelista Falcón W. The Role of Protein Structural Ensembles in Thermostability and Ligand Binding. [Doctoral Dissertation]. University of Tennessee – Knoxville; 2017. Available from: https://trace.tennessee.edu/utk_graddiss/4854

Virginia Tech

18. Kappiyoor, Ravi. Mechanical Properties of Elastomeric Proteins.

Degree: PhD, Engineering Science and Mechanics, 2014, Virginia Tech

URL: http://hdl.handle.net/10919/54563

► When we stretch and contract a rubber band a hundred times, we expect the rubber band to fail. Yet our heart stretches and contracts the… (more)

Subjects/Keywords: Protein elasticity; molecular dynamics; nanoscale material properties

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APA (6^th Edition):

Kappiyoor, R. (2014). Mechanical Properties of Elastomeric Proteins. (Doctoral Dissertation). Virginia Tech. Retrieved from http://hdl.handle.net/10919/54563

Chicago Manual of Style (16^th Edition):

Kappiyoor, Ravi. “Mechanical Properties of Elastomeric Proteins.” 2014. Doctoral Dissertation, Virginia Tech. Accessed August 24, 2019. http://hdl.handle.net/10919/54563.

MLA Handbook (7^th Edition):

Kappiyoor, Ravi. “Mechanical Properties of Elastomeric Proteins.” 2014. Web. 24 Aug 2019.

Vancouver:

Kappiyoor R. Mechanical Properties of Elastomeric Proteins. [Internet] [Doctoral dissertation]. Virginia Tech; 2014. [cited 2019 Aug 24]. Available from: http://hdl.handle.net/10919/54563.

Council of Science Editors:

Kappiyoor R. Mechanical Properties of Elastomeric Proteins. [Doctoral Dissertation]. Virginia Tech; 2014. Available from: http://hdl.handle.net/10919/54563

Princeton University

19. Sun, Xun. Functional Conformational Dynamics in Complex Protein Systems .

Degree: PhD, 2016, Princeton University

URL: http://arks.princeton.edu/ark:/88435/dsp01k35696731

► Proteins are remarkable nano-scale molecular machinery; they are involved in almost all life processes by performing assorted functions in the presence of thermal fluctuations from… (more)

▼ Proteins are remarkable nano-scale molecular machinery; they are involved in almost all life processes by performing assorted functions in the presence of thermal fluctuations from their environments. The coupling between solvent fluctuations and a protein is of particular importance to the protein’s large amplitude motions on μs-toms timescales, which largely overlap with the timescales of protein-protein interactions and enzymatic turnovers. Understanding the functional roles of conformational dynamics in complex protein systems demands quantitative measurements and rigorous interpretations of protein conformational distributions. Single-molecule Forster resonance energy transfer (smFRET) has emerged as a powerful technique to reveal conformational distributions by removing the ensemble averaging. It is shown in this work that a set of orthogonal conformational modes—that afford a linear combination to describe conformational dynamics—are contained in experimentally measured conformational distributions. To contextualize conformational modes and their potential functional roles, two specific examples, gramicidin S synthetase A (GrsA) and human insulin-degrading enzyme (IDE), are studied. Application of high-resolution smFRET, time-dependent bulk FRET spectroscopy, kinetics profiling and structural modeling shows that the adenylation-thioesterification cascade is gated by the conformational transitions in the adenylation and peptide carrier protein domains in GrsA. Such conformational transitions occur via the newly identified on-pathway intermediate conformations. In the case of IDE, integration of the multiple smFRET mapping and a newly developed statistical sampling framework enables the structural computation and the extraction of predominant conformational modes in a data-driven manner from multiple smFRET distance distributions. Compared to IDE monomer, the protein-protein interaction in IDE dimer profoundly alters the conformational modes and confines the motion amplitudes. These motions could allow IDE to populate in the hitherto undetermined open conformations to complete the catalytic cycle. That these modes are similar to those from the elastic network modeling for both IDE monomer and dimer suggests that large-amplitude motions could be directly encoded in three-dimension protein architectures in complex protein systems. It is anticipated that the multi-platform biophysical experimentation and statistical framework presented here could be generalized to visualize and probe conformational modes, or more generally, dynamic molecular structures in other complex protein systems of interest. Advisors/Committee Members: Yang, Haw (advisor).

Subjects/Keywords: Bayesian statistics; protein dynamics; single-molecule FRET

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APA (6^th Edition):

Sun, X. (2016). Functional Conformational Dynamics in Complex Protein Systems . (Doctoral Dissertation). Princeton University. Retrieved from http://arks.princeton.edu/ark:/88435/dsp01k35696731

Chicago Manual of Style (16^th Edition):

Sun, Xun. “Functional Conformational Dynamics in Complex Protein Systems .” 2016. Doctoral Dissertation, Princeton University. Accessed August 24, 2019. http://arks.princeton.edu/ark:/88435/dsp01k35696731.

MLA Handbook (7^th Edition):

Sun, Xun. “Functional Conformational Dynamics in Complex Protein Systems .” 2016. Web. 24 Aug 2019.

Vancouver:

Sun X. Functional Conformational Dynamics in Complex Protein Systems . [Internet] [Doctoral dissertation]. Princeton University; 2016. [cited 2019 Aug 24]. Available from: http://arks.princeton.edu/ark:/88435/dsp01k35696731.

Council of Science Editors:

Sun X. Functional Conformational Dynamics in Complex Protein Systems . [Doctoral Dissertation]. Princeton University; 2016. Available from: http://arks.princeton.edu/ark:/88435/dsp01k35696731

University of Texas – Austin

20. Shahmoradi, Amir. Dissecting the relationship between protein structure and sequence evolution.

Degree: Physics, 2015, University of Texas – Austin

URL: http://hdl.handle.net/2152/31639

► What can protein structure tell us about protein evolutionary dynamics? Despite extensive variety in their native structures, from hyper-thermostable to intrinsically disordered, all proteins share… (more)

▼ What can protein structure tell us about protein evolutionary dynamics? Despite extensive variety in their native structures, from hyper-thermostable to intrinsically disordered, all proteins share a common feature: flexibility and dynamics at different levels of structure. In addition to spatial dynamics, proteins are also highly evolutionary dynamic polymers, exhibiting variability in their amino acid sequences on evolutionary timescales. Significant variations can be observed in the amino acid sequences of the divergent members of a single protein family, while their native conformations and biological functions remain almost conserved among all members of the family. These evolutionary variations can be due to a combination of point mutations, insertions, deletions or sometimes the rearrangement of domains in the protein sequence. In recent years, it has become increasingly evident that the dynamics of proteins in space and time domains – corresponding to structural and evolutionary variations – mutually influence each other at the amino acid level. In particular, it is generally observed that the amino acids in the core of protein are more conserved than the amino acids on the surface. Some site-specific structural quantities have been already identified that are capable of explaining the general patterns of sequence variability in globular proteins. A prominent example is the amino acid exposure to solvent molecules – typically water – which surround proteins in vivo. Furthermore, some partial associations between the local flexibility, packing density and sequence variability can be also observed among globular proteins. There is however no consensus as to which set of structural characteristics play the dominant role in sequence evolution. The strength of sequence – structure correlations also appear to vary widely from one protein to another, with Spearman's correlation strength ρ ∈ [0.1,0.8]. Throughout a series of works summarized in the following chapters, first I explore the wide spectrum of structural determinants of sequence evolution, their interrelationships, and their role in the evolutionary dynamics of protein. I find that amino acid sites that are important for the overall stability of protein structure in general tend to be highly conserved. In other words, any amino acid substitution that results in a significant change of the potential energy landscape and thus the native conformation of protein, is disruptive and hence occurs less frequently on evolutionary timescale. I also find that long-range interactions among individual amino acids play a weak but non-negligible role in site-specific evolution of proteins and their inclusion generally results in better predictions of sequence evolution from protein structure. Then, I present the results from a comprehensive search for the potential biophysical and structural determinants of protein evolution by studying >200 structural and evolutionary characteristics of proteins in a dataset of viral and enzymatic proteins. I discuss the main… Advisors/Committee Members: Mahajan, Swadesh M. (advisor), Wilke, C. (Claus) (advisor), Orbach, Raymond L (committee member), Marder, Michael P (committee member), Gordon, Vernita D (committee member), Press, William H (committee member).

Subjects/Keywords: Biophysics; Evolutionary biology; Protein dynamics; Viral evolution

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APA (6^th Edition):

Shahmoradi, A. (2015). Dissecting the relationship between protein structure and sequence evolution. (Thesis). University of Texas – Austin. Retrieved from http://hdl.handle.net/2152/31639

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Shahmoradi, Amir. “Dissecting the relationship between protein structure and sequence evolution.” 2015. Thesis, University of Texas – Austin. Accessed August 24, 2019. http://hdl.handle.net/2152/31639.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Shahmoradi, Amir. “Dissecting the relationship between protein structure and sequence evolution.” 2015. Web. 24 Aug 2019.

Vancouver:

Shahmoradi A. Dissecting the relationship between protein structure and sequence evolution. [Internet] [Thesis]. University of Texas – Austin; 2015. [cited 2019 Aug 24]. Available from: http://hdl.handle.net/2152/31639.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Shahmoradi A. Dissecting the relationship between protein structure and sequence evolution. [Thesis]. University of Texas – Austin; 2015. Available from: http://hdl.handle.net/2152/31639

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Utah State University

21. Moise, Gwendolyn. Investigations into Factors Affecting the WPD-Loop in the Protein Tyrosine Phosphatases YopH and PTP1B.

Degree: PhD, Chemistry and Biochemistry, 2018, Utah State University

URL: https://digitalcommons.usu.edu/etd/7226

► The research in this dissertation documents connections between the primary amino acid sequence of proteins, the dynamics of proteins, and their catalytic function. This… (more)

Subjects/Keywords: PTP; hydrolase; kenetics; protein; dynamics; Chemistry

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APA (6^th Edition):

Moise, G. (2018). Investigations into Factors Affecting the WPD-Loop in the Protein Tyrosine Phosphatases YopH and PTP1B. (Doctoral Dissertation). Utah State University. Retrieved from https://digitalcommons.usu.edu/etd/7226

Chicago Manual of Style (16^th Edition):

Moise, Gwendolyn. “Investigations into Factors Affecting the WPD-Loop in the Protein Tyrosine Phosphatases YopH and PTP1B.” 2018. Doctoral Dissertation, Utah State University. Accessed August 24, 2019. https://digitalcommons.usu.edu/etd/7226.

MLA Handbook (7^th Edition):

Moise, Gwendolyn. “Investigations into Factors Affecting the WPD-Loop in the Protein Tyrosine Phosphatases YopH and PTP1B.” 2018. Web. 24 Aug 2019.

Vancouver:

Moise G. Investigations into Factors Affecting the WPD-Loop in the Protein Tyrosine Phosphatases YopH and PTP1B. [Internet] [Doctoral dissertation]. Utah State University; 2018. [cited 2019 Aug 24]. Available from: https://digitalcommons.usu.edu/etd/7226.

Council of Science Editors:

Moise G. Investigations into Factors Affecting the WPD-Loop in the Protein Tyrosine Phosphatases YopH and PTP1B. [Doctoral Dissertation]. Utah State University; 2018. Available from: https://digitalcommons.usu.edu/etd/7226

Rice University

22. Eddy, Nathanial Reed. On the role of conformational flexibility in viral fusion mechanisms - fusion by disorder.

Degree: PhD, Natural Sciences, 2018, Rice University

URL: http://hdl.handle.net/1911/105758

► Viral diseases continue to contribute to leading causes of death around the world and are annually responsible for significant morbidity and mortality. Many envelope viruses… (more)

▼ Viral diseases continue to contribute to leading causes of death around the world and are annually responsible for significant morbidity and mortality. Many envelope viruses infect cells through the use of fusion proteins, surface proteins which are responsible for fusing the viral and host membranes through large scale conformational transitions. Although pre-fusion and post-fusion structures have been experimentally determined for many viral fusion proteins, specific structural details about how they transition between these states have remained challenging to probe both experimentally and computationally. Even with recent computational advances, acquiring equilibrium distributions of the entire functional landscape through standard molecular dynamics calculations is not currently feasible. In this body of work, we employ structure based models to analyze the conformational dynamics of a range of viral fusion proteins. Structure based models have rigorous mathematical roots in the language of energy landscape theory and have been successfully applied to many problems in folding, allostery, and functional motions of biomolecules. These models take experimental structures as an input and make them explicit energy minima in the Hamiltonian. We construct energy functions for several viral fusion proteins which simultaneously include all interactions from the pre- and post-fusion structures and observe their time evolution. We first analyze Influenza A Hemagglutinin, where we show that Hemagglutinin can transition by two dominant pathways. Both pathways are characterized by an early order-disorder transition in a characteristic hairpin region and breaking of the threefold symmetry present in the prefusion structure. Late stage N-C terminal zipping completes the transition. This picture is in contrast with the standard spring-loaded view of Hemagglutinin mediated fusion, where an early loop to helix transition drives the transition. We extend this analysis to a survey of other Class I viral fusion proteins and show that they all share the same global mechanistic features observed in Hemagglutinin. Finally, we employ a similar model to investigate Class II Dengue Envelope dimers and show that symmetry in the potential gives rise to a dynamic, entropically stabilized intermediate state. Collectively, these results are suggestive that viruses take advantage of conformational flexibility and disordered intermediate ensembles to facilitate viral entry. Advisors/Committee Members: Onuchic, José N (advisor).

Subjects/Keywords: viral fusion; conformational dynamics; protein folding; hemagglutinin

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APA (6^th Edition):

Eddy, N. R. (2018). On the role of conformational flexibility in viral fusion mechanisms - fusion by disorder. (Doctoral Dissertation). Rice University. Retrieved from http://hdl.handle.net/1911/105758

Chicago Manual of Style (16^th Edition):

Eddy, Nathanial Reed. “On the role of conformational flexibility in viral fusion mechanisms - fusion by disorder.” 2018. Doctoral Dissertation, Rice University. Accessed August 24, 2019. http://hdl.handle.net/1911/105758.

MLA Handbook (7^th Edition):

Eddy, Nathanial Reed. “On the role of conformational flexibility in viral fusion mechanisms - fusion by disorder.” 2018. Web. 24 Aug 2019.

Vancouver:

Eddy NR. On the role of conformational flexibility in viral fusion mechanisms - fusion by disorder. [Internet] [Doctoral dissertation]. Rice University; 2018. [cited 2019 Aug 24]. Available from: http://hdl.handle.net/1911/105758.

Council of Science Editors:

Eddy NR. On the role of conformational flexibility in viral fusion mechanisms - fusion by disorder. [Doctoral Dissertation]. Rice University; 2018. Available from: http://hdl.handle.net/1911/105758

23. Foster, Leigh Suzanne Holmes. The effect of sequence and environment on the structure and dimerization of amyloid precursor protein.

Degree: PhD, Chemistry, 2015, Boston University

URL: http://hdl.handle.net/2144/15180

► Aggregation of amyloid β (Aβ) protein has been linked to the development of Alzheimer's Disease (AD). The genesis of Aβ involves the cleavage Amyloid Precursor… (more)

▼ Aggregation of amyloid β (Aβ) protein has been linked to the development of Alzheimer's Disease (AD). The genesis of Aβ involves the cleavage Amyloid Precursor Protein (APP) by β-secretase, producing the 99-residue C99 peptide, and the subsequent cleavage of C99 by γ-secretase to produce Aβ. A detailed understanding of the γ-cleavage process is essential to our undertsanding of the pathological mechanisms linking the aggregation of Aβ to the development of AD. This work seeks to provide insight into critical aspects of the structure and dynamics of C99, and the particular roles played by (1) C99 amino acid sequence and (2) the lipid composition of the membrane environment. Many studies have focused on the importance of the C99 sequence, including known studies of Familial AD (FAD) mutants as well as engineered mutations. Specific mutations have been found to affect the processing of C99, which has been linked to changes in the structure of C99 and the formation of C99 homodimers. Similarly, changes in the membrane environment, through variation in lipid composition and the presence of cholesterol, have been found to affect C99 structure and positioning within the membrane as well as C99 dimerization. The results of this work extend our understanding of the APP-C99 system and its interaction with the environment. Using a multiscale simulation approach, we find key structural effects of engineered mutations that suggest possible mechanistic insight into the γ-cleavage process. Using C99 congener peptides, we examine the effect of local membrane environment on the dimerization of C99, focusing on the roles of both the transmembrane (TM) region as well as the juxtamembrane (JM) domain. Further studies characterize the role of a FAD mutation, and demonstrate the effect of the mutation on the dimerization of C99 in agreement with experimental findings. Overall, this work leads to critical insight into the role of sequence and membrane on the structure of C99 in a membrane environment, and provides support for the conjecture that the structure of C99 monomer and homodimer are critical to our understanding of the processing of C99, a critical step in the genesis of Aβ peptide and the etiology of Alzheimer's Disease.

Subjects/Keywords: Chemistry; Computational chemistry; Molecular dynamics; Protein structure

11 more images…

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APA (6^th Edition):

Foster, L. S. H. (2015). The effect of sequence and environment on the structure and dimerization of amyloid precursor protein. (Doctoral Dissertation). Boston University. Retrieved from http://hdl.handle.net/2144/15180

Chicago Manual of Style (16^th Edition):

Foster, Leigh Suzanne Holmes. “The effect of sequence and environment on the structure and dimerization of amyloid precursor protein.” 2015. Doctoral Dissertation, Boston University. Accessed August 24, 2019. http://hdl.handle.net/2144/15180.

MLA Handbook (7^th Edition):

Foster, Leigh Suzanne Holmes. “The effect of sequence and environment on the structure and dimerization of amyloid precursor protein.” 2015. Web. 24 Aug 2019.

Vancouver:

Foster LSH. The effect of sequence and environment on the structure and dimerization of amyloid precursor protein. [Internet] [Doctoral dissertation]. Boston University; 2015. [cited 2019 Aug 24]. Available from: http://hdl.handle.net/2144/15180.

Council of Science Editors:

Foster LSH. The effect of sequence and environment on the structure and dimerization of amyloid precursor protein. [Doctoral Dissertation]. Boston University; 2015. Available from: http://hdl.handle.net/2144/15180

University of Minnesota

24. Li, Geoffrey. On the Role of Conformational Dynamics in Allostery and Cooperativity in Protein Kinase A.

Degree: PhD, Chemistry, 2017, University of Minnesota

URL: http://hdl.handle.net/11299/195388

► Protein kinases are a large class of enzymes that regulate a wide array of vital cellular processes. Their dysregulation has been associated with fatal diseases… (more)

Subjects/Keywords: allostery; conformational dynamics; cooperativity; NMR; protein kinase

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APA (6^th Edition):

Li, G. (2017). On the Role of Conformational Dynamics in Allostery and Cooperativity in Protein Kinase A. (Doctoral Dissertation). University of Minnesota. Retrieved from http://hdl.handle.net/11299/195388

Chicago Manual of Style (16^th Edition):

Li, Geoffrey. “On the Role of Conformational Dynamics in Allostery and Cooperativity in Protein Kinase A.” 2017. Doctoral Dissertation, University of Minnesota. Accessed August 24, 2019. http://hdl.handle.net/11299/195388.

MLA Handbook (7^th Edition):

Li, Geoffrey. “On the Role of Conformational Dynamics in Allostery and Cooperativity in Protein Kinase A.” 2017. Web. 24 Aug 2019.

Vancouver:

Li G. On the Role of Conformational Dynamics in Allostery and Cooperativity in Protein Kinase A. [Internet] [Doctoral dissertation]. University of Minnesota; 2017. [cited 2019 Aug 24]. Available from: http://hdl.handle.net/11299/195388.

Council of Science Editors:

Li G. On the Role of Conformational Dynamics in Allostery and Cooperativity in Protein Kinase A. [Doctoral Dissertation]. University of Minnesota; 2017. Available from: http://hdl.handle.net/11299/195388

University of Southern California

25. Lin, Chih-Ying. Molecular dynamics simulation study of initial protein unfolding induced by the photo-responsive surfactants, azoTAB.

Degree: PhD, Chemical Engineering, 2014, University of Southern California

URL: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll3/id/364713/rec/4179

► How proteins fold and unfold has been a great focus for decades. Techniques of molecular dynamics simulations provide the atomic insight of protein folding/unfolding. Proteins… (more)

Subjects/Keywords: molecular dynamics; simulations; protein; surfactants; folding; unfolding

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APA (6^th Edition):

Lin, C. (2014). Molecular dynamics simulation study of initial protein unfolding induced by the photo-responsive surfactants, azoTAB. (Doctoral Dissertation). University of Southern California. Retrieved from http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll3/id/364713/rec/4179

Chicago Manual of Style (16^th Edition):

Lin, Chih-Ying. “Molecular dynamics simulation study of initial protein unfolding induced by the photo-responsive surfactants, azoTAB.” 2014. Doctoral Dissertation, University of Southern California. Accessed August 24, 2019. http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll3/id/364713/rec/4179.

MLA Handbook (7^th Edition):

Lin, Chih-Ying. “Molecular dynamics simulation study of initial protein unfolding induced by the photo-responsive surfactants, azoTAB.” 2014. Web. 24 Aug 2019.

Vancouver:

Lin C. Molecular dynamics simulation study of initial protein unfolding induced by the photo-responsive surfactants, azoTAB. [Internet] [Doctoral dissertation]. University of Southern California; 2014. [cited 2019 Aug 24]. Available from: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll3/id/364713/rec/4179.

Council of Science Editors:

Lin C. Molecular dynamics simulation study of initial protein unfolding induced by the photo-responsive surfactants, azoTAB. [Doctoral Dissertation]. University of Southern California; 2014. Available from: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll3/id/364713/rec/4179

26. Morriss-Andrews, Herbert Alexander. Coarse-Grained Molecular Dynamics Simulations of Peptide Aggregation on Surfaces.

Degree: 2014, University of California – eScholarship, University of California

URL: http://www.escholarship.org/uc/item/2ms586vt

► Protein aggregation involves self-assembly of normally soluble proteins or peptides into supramolecular structures. This process is particularly important due to its involvement in several amyloid… (more)

▼ Protein aggregation involves self-assembly of normally soluble proteins or peptides into supramolecular structures. This process is particularly important due to its involvement in several amyloid diseases, such as Parkinson's, Alzheimer's, and Type II diabetes. Several fibrillization mechanisms have been proposed, including a condensation-ordering mechanism where ordered fibril structures emerge from disordered oligomers and a dock-lock mechanism where a growing fibril induces attached polypeptides to organize individually into fibril-compatible conformations.We present a series of computational studies using a coarse-grained peptide aggregate model that exhibits a rich diversity of structures: amorphous/disordered aggregates, beta-barrels, multi-layered fibrils, and aggregates of mixed type. Our model has a tunable backbone stiffness that governs the propensity to form fibrils in bulk solution. In this work, we investigate how this beta-sheet propensity couples with the properties of a surface template to influence the mechanism of aggregation. Here, we focus on peptide aggregation in the presence of three templates: a solid surface, the surface of a pre-existing aggregate seed, and a lipid bilayer. Aggregation on solid hydrophilic or hydrophobic surfaces frequently occurs in many experimental setups. We find that the solid surface strongly biases toward the formation of fibrillar aggregates. Peptide-peptide interactions and surface attraction couple cooperatively on a solid surface to influence the binding/aggregation transition. Aggregation and binding occur almost simultaneously since the surface's crystal symmetry enforces a preferred direction of bound fibril growth, thus accelerating the process.Seeding peptides with compatible aggregates removes the nucleation barrier for aggregation. We find that the aggregation mechanism is strongly dependent on the beta-sheet propensity of both the seed and bulk peptides. Additionally, bulk peptides that exhibit polymorphism can have multiple pathways to aggregation depending on which class of aggregate they initially form. We find that a fibrillar seed can induce amorphous-prone peptides into fibrillar structures via a condensation-ordering mechanism, thus sequestering potentially cytotoxic oligomers into a more inert form.We simulate aggregation on lipid bilayers in an effort to approximate the complexity of the cellular milieu. While aggregation in vivo would occur in the presence of membrane surfaces, few simulation studies have been conducted on this combined system due to its computational complexity. We have determined that a membrane surface, like a crystal surface, biases toward fibrillar aggregates. However, membrane undulations disturb multi-layered fibrils into non-planar beta-sheet structures, such as beta-barrels. The presence of fibrils on the membrane also affects its fluid properties, creating a hexagonally packed lipid ordering underneath the fibrils, locally increasing its bending modulus and aligning lipid tilt to the orientation of the peptides. Thus…

Subjects/Keywords: Biophysics; Aggregation; Membranes; Molecular Dynamics; Protein; Simulation

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APA (6^th Edition):

Morriss-Andrews, H. A. (2014). Coarse-Grained Molecular Dynamics Simulations of Peptide Aggregation on Surfaces. (Thesis). University of California – eScholarship, University of California. Retrieved from http://www.escholarship.org/uc/item/2ms586vt

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Morriss-Andrews, Herbert Alexander. “Coarse-Grained Molecular Dynamics Simulations of Peptide Aggregation on Surfaces.” 2014. Thesis, University of California – eScholarship, University of California. Accessed August 24, 2019. http://www.escholarship.org/uc/item/2ms586vt.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Morriss-Andrews, Herbert Alexander. “Coarse-Grained Molecular Dynamics Simulations of Peptide Aggregation on Surfaces.” 2014. Web. 24 Aug 2019.

Vancouver:

Morriss-Andrews HA. Coarse-Grained Molecular Dynamics Simulations of Peptide Aggregation on Surfaces. [Internet] [Thesis]. University of California – eScholarship, University of California; 2014. [cited 2019 Aug 24]. Available from: http://www.escholarship.org/uc/item/2ms586vt.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Morriss-Andrews HA. Coarse-Grained Molecular Dynamics Simulations of Peptide Aggregation on Surfaces. [Thesis]. University of California – eScholarship, University of California; 2014. Available from: http://www.escholarship.org/uc/item/2ms586vt

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Arizona State University

27. Glembo, Tyler. The Role of Mutations in Protein Structural Dynamics and Function: A Multi-scale Computational Approach.

Degree: PhD, Physics, 2011, Arizona State University

URL: http://repository.asu.edu/items/9515

► Proteins are a fundamental unit in biology. Although proteins have been extensively studied, there is still much to investigate. The mechanism by which proteins fold… (more)

▼ Proteins are a fundamental unit in biology. Although proteins have been extensively studied, there is still much to investigate. The mechanism by which proteins fold into their native state, how evolution shapes structural dynamics, and the dynamic mechanisms of many diseases are not well understood. In this thesis, protein folding is explored using a multi-scale modeling method including (i) geometric constraint based simulations that efficiently search for native like topologies and (ii) reservoir replica exchange molecular dynamics, which identify the low free energy structures and refines these structures toward the native conformation. A test set of eight proteins and three ancestral steroid receptor proteins are folded to 2.7Å all-atom RMSD from their experimental crystal structures. Protein evolution and disease associated mutations (DAMs) are most commonly studied by in silico multiple sequence alignment methods. Here, however, the structural dynamics are incorporated to give insight into the evolution of three ancestral proteins and the mechanism of several diseases in human ferritin protein. The differences in conformational dynamics of these evolutionary related, functionally diverged ancestral steroid receptor proteins are investigated by obtaining the most collective motion through essential dynamics. Strikingly, this analysis shows that evolutionary diverged proteins of the same family do not share the same dynamic subspace. Rather, those sharing the same function are simultaneously clustered together and distant from those functionally diverged homologs. This dynamics analysis also identifies 77% of mutations (functional and permissive) necessary to evolve new function. In silico methods for prediction of DAMs rely on differences in evolution rate due to purifying selection and therefore the accuracy of DAM prediction decreases at fast and slow evolvable sites. Here, we investigate structural dynamics through computing the contribution of each residue to the biologically relevant fluctuations and from this define a metric: the dynamic stability index (DSI). Using DSI we study the mechanism for three diseases observed in the human ferritin protein. The T30I and R40G DAMs show a loss of dynamic stability at the C-terminus helix and nearby regulatory loop, agreeing with experimental results implicating the same regulatory loop as a cause in cataracts syndrome.

Subjects/Keywords: Biophysics; dynamics; evolution; function; mutation; protein; structure

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Glembo, T. (2011). The Role of Mutations in Protein Structural Dynamics and Function: A Multi-scale Computational Approach. (Doctoral Dissertation). Arizona State University. Retrieved from http://repository.asu.edu/items/9515

Chicago Manual of Style (16^th Edition):

Glembo, Tyler. “The Role of Mutations in Protein Structural Dynamics and Function: A Multi-scale Computational Approach.” 2011. Doctoral Dissertation, Arizona State University. Accessed August 24, 2019. http://repository.asu.edu/items/9515.

MLA Handbook (7^th Edition):

Glembo, Tyler. “The Role of Mutations in Protein Structural Dynamics and Function: A Multi-scale Computational Approach.” 2011. Web. 24 Aug 2019.

Vancouver:

Glembo T. The Role of Mutations in Protein Structural Dynamics and Function: A Multi-scale Computational Approach. [Internet] [Doctoral dissertation]. Arizona State University; 2011. [cited 2019 Aug 24]. Available from: http://repository.asu.edu/items/9515.

Council of Science Editors:

Glembo T. The Role of Mutations in Protein Structural Dynamics and Function: A Multi-scale Computational Approach. [Doctoral Dissertation]. Arizona State University; 2011. Available from: http://repository.asu.edu/items/9515

University of California – Irvine

28. Fields, James Burton. Protein Association in the Membrane, Mitochondria, and Cytosol: Results from Combined Brownian and Molecular Dynamics Studies.

Degree: Chemistry, 2017, University of California – Irvine

URL: http://www.escholarship.org/uc/item/9s01z96d

► Protein-protein interactions (PPIs) play a crucial role in the regulation of protein activity, and are therefor of great importance in biology. Interactions between proteins require… (more)

Subjects/Keywords: Physical chemistry; Biophysics; Biophysics; Brownian Dynamics; Membrane Protein; Molecular Dynamics; Protein Association

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Fields, J. B. (2017). Protein Association in the Membrane, Mitochondria, and Cytosol: Results from Combined Brownian and Molecular Dynamics Studies. (Thesis). University of California – Irvine. Retrieved from http://www.escholarship.org/uc/item/9s01z96d

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Fields, James Burton. “Protein Association in the Membrane, Mitochondria, and Cytosol: Results from Combined Brownian and Molecular Dynamics Studies.” 2017. Thesis, University of California – Irvine. Accessed August 24, 2019. http://www.escholarship.org/uc/item/9s01z96d.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Fields, James Burton. “Protein Association in the Membrane, Mitochondria, and Cytosol: Results from Combined Brownian and Molecular Dynamics Studies.” 2017. Web. 24 Aug 2019.

Vancouver:

Fields JB. Protein Association in the Membrane, Mitochondria, and Cytosol: Results from Combined Brownian and Molecular Dynamics Studies. [Internet] [Thesis]. University of California – Irvine; 2017. [cited 2019 Aug 24]. Available from: http://www.escholarship.org/uc/item/9s01z96d.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Fields JB. Protein Association in the Membrane, Mitochondria, and Cytosol: Results from Combined Brownian and Molecular Dynamics Studies. [Thesis]. University of California – Irvine; 2017. Available from: http://www.escholarship.org/uc/item/9s01z96d

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of Manitoba

29. To, Vu. Backbone dynamics of the intrinsically disordered HIV-1 Tat protein.

Degree: Chemistry, 2017, University of Manitoba

URL: http://hdl.handle.net/1993/32353

► The type 1 Human Immunodeficiency Virus (HIV-1) transactivator of transcription (Tat) is a 101-residue protein that significantly increases the viral transcription. The full-length Tat protein… (more)

▼ The type 1 Human Immunodeficiency Virus (HIV-1) transactivator of transcription (Tat) is a 101-residue protein that significantly increases the viral transcription. The full-length Tat protein (Tat101) is encoded by two exons yielding the first 72 and the last 29 residues of the protein, respectively. The function and intrinsic disorder of the first 72 residues have been studied in great detail but relatively little is known about the structure and function of the second exon product despite its conserved expression in all lentiviruses. My thesis aims to study the impact of Tat’s second exon product on the full-length protein in terms of disorder, dynamics and structural propensity. NMR spectroscopy has been used to study Tat101 protein in a fully reduced state. Multiple isotope labeling strategies were applied and the labeled protein was expressed and purified in high yield. Backbone resonance assignment, chemical shift analysis, structure propensity analysis, fast (ps-ns) and slow (ms) timescale dynamics and hydrogen exchange studies confirm the intrinsically disordered nature of the second exon product and full-length Tat. The NMR results revealed Tat’s propensities to adopt different local conformations. Reduced spectral density mapping and model-free analysis show that the fast internal motion on the ps-ns timescale dominates the relaxation, and that Tat101 has no slow motion / conformational exchange on the ms timescale. The hydrogen exchange measurements yield protection factors below 1, which can be explained by the higher local pH compared with the bulk solvent. Classical molecular dynamics simulations were used as a complementary technique to verify the NMR results and to sample the protein conformers that are invisible to NMR due to ensemble averaging. The two 100 ns trajectories from the simulations of Tat’s first exon product are dominated by non-structural elements such as coils, turns, and bends. The order parameters derived from the simulations are below 0.8 and in agreement with the NMR results, confirming the flexibility of the protein. The combination of NMR dynamics and simulation results indicate that some regions of the protein likely bind partners through a conformational-selection mechanism while other parts of protein bind their targets through an induced-fit mechanism. Advisors/Committee Members: O'Neil, Joe (Chemistry) (supervisor), McKenna, Sean (Chemistry).

Subjects/Keywords: HIV; Intrinsically disordered protein; Transactivator of transcription; Protein dynamics; Molecular dynamics simulation; NMR

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

To, V. (2017). Backbone dynamics of the intrinsically disordered HIV-1 Tat protein. (Thesis). University of Manitoba. Retrieved from http://hdl.handle.net/1993/32353

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

To, Vu. “Backbone dynamics of the intrinsically disordered HIV-1 Tat protein.” 2017. Thesis, University of Manitoba. Accessed August 24, 2019. http://hdl.handle.net/1993/32353.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

To, Vu. “Backbone dynamics of the intrinsically disordered HIV-1 Tat protein.” 2017. Web. 24 Aug 2019.

Vancouver:

To V. Backbone dynamics of the intrinsically disordered HIV-1 Tat protein. [Internet] [Thesis]. University of Manitoba; 2017. [cited 2019 Aug 24]. Available from: http://hdl.handle.net/1993/32353.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

To V. Backbone dynamics of the intrinsically disordered HIV-1 Tat protein. [Thesis]. University of Manitoba; 2017. Available from: http://hdl.handle.net/1993/32353

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Univerzitet u Beogradu

30. Ranđelović, Jelena N., 1986-. Dizajniranje peptidnih i nepeptidnih inhibitora proteinskih interakcija ciklin-zavisne kinaze 9 i ciklina T1 primenom računarskih metoda.

Degree: Farmaceutski fakultet, 2014, Univerzitet u Beogradu

URL: https://fedorabg.bg.ac.rs/fedora/get/o:7216/bdef:Content/get

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Farmaceutske nauke - Farmaceutska hemija / Pharmaceutical Sciences - Medicinal Chemistry

Cilj ove doktorske disertacije je razvoj direktnih inhibitora interakcija u kompleksu CDK9 / ciklin… (more)

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Farmaceutske nauke - Farmaceutska hemija / Pharmaceutical Sciences - Medicinal Chemistry

Cilj ove doktorske disertacije je razvoj direktnih inhibitora interakcija u kompleksu CDK9 / ciklin T1. Ciklin zavisna kinaza 9 u kompleksu sa ciklinom T1 čini katalitičko jezgro P-TEFb kompleksa. Inhibicija funkcije P-TEFb kompleksa je od značaja u terapiji više patoloških stanja kod ljudi: nekih tipova maligniteta, HIV-1 infekcije, hipertrofije miokarda, hroničnih inflamatornih bolesti. Postojeći inhibitori P-TEFb funkcije imaju ograničenu selektivnost dejstva, koju je moguće poboljšati primenom direktnih inhibitora CDK9 / ciklin T1 interakcije. U ovom istraživanju urađena je in silico studija P-TEFb kompleksa. Ispitana je struktura, hidratisanost i dinamika vezivnih površina kompleksa. Utvrđene su energetski najznačajnije hot spot aminokiseline u strukturi kompleksa i upotrebljene za dalji dizajn inhibitora. Struktura slobodne CDK9, neophodna za dizajn liganada je, u nedostatku eksperimentalno utvrđene strukture, simulirana klasičnom i ubrzanom molekularnom dinamikom. Ispitana je sposobnost vezivne površine kompleksa da interaguje sa ligandima, kao i postojanje, otvaranje i postojanost privremenih hidrofobnih džepova na vezivnoj površini CDK9, pogodnih za vezivanje liganada. Dobijene informacije o vezivnim površinama kompleksa CDK9 / ciklin T1, upotrebljene su za dizajn peptidnih i nepeptidnih inhibitora interakcije. Peptidni inhibitori su dizajnirani po ugledu na strukturu ciklina T1, ali i de novo dizajnom iz aminokiselina. Peptidne strukture sa najpovoljnijom energijom vezivanja za CDK9, iskorišćene su u razvoju nepeptidnih inhibitora. Predložene su strukture potencijalnih nepeptidnih inhibitora interakcije CDK9 / ciklin T1. U okviru ovog istraživanja urađeno je i ab initio ispitivanje prelaznih stanja intramolekulske Heck-ove ciklizacije alilnih alkohola i predloženo je objašnjenje za eksperimentalno zapaženu regioselektivnost procesa.

Advisors/Committee Members: Savić, Vladimir, 1963-.

Subjects/Keywords: protein-protein interactions; CDK9 / cyclin T1; molecular dynamics

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Ranđelović, Jelena N., 1. (2014). Dizajniranje peptidnih i nepeptidnih inhibitora proteinskih interakcija ciklin-zavisne kinaze 9 i ciklina T1 primenom računarskih metoda. (Thesis). Univerzitet u Beogradu. Retrieved from https://fedorabg.bg.ac.rs/fedora/get/o:7216/bdef:Content/get

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Ranđelović, Jelena N., 1986-. “Dizajniranje peptidnih i nepeptidnih inhibitora proteinskih interakcija ciklin-zavisne kinaze 9 i ciklina T1 primenom računarskih metoda.” 2014. Thesis, Univerzitet u Beogradu. Accessed August 24, 2019. https://fedorabg.bg.ac.rs/fedora/get/o:7216/bdef:Content/get.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Ranđelović, Jelena N., 1986-. “Dizajniranje peptidnih i nepeptidnih inhibitora proteinskih interakcija ciklin-zavisne kinaze 9 i ciklina T1 primenom računarskih metoda.” 2014. Web. 24 Aug 2019.

Vancouver:

Ranđelović, Jelena N. 1. Dizajniranje peptidnih i nepeptidnih inhibitora proteinskih interakcija ciklin-zavisne kinaze 9 i ciklina T1 primenom računarskih metoda. [Internet] [Thesis]. Univerzitet u Beogradu; 2014. [cited 2019 Aug 24]. Available from: https://fedorabg.bg.ac.rs/fedora/get/o:7216/bdef:Content/get.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Ranđelović, Jelena N. 1. Dizajniranje peptidnih i nepeptidnih inhibitora proteinskih interakcija ciklin-zavisne kinaze 9 i ciklina T1 primenom računarskih metoda. [Thesis]. Univerzitet u Beogradu; 2014. Available from: https://fedorabg.bg.ac.rs/fedora/get/o:7216/bdef:Content/get

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Open Access Theses and Dissertations