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Vanderbilt University
1.
Li, Bian.
Structure prediction and variant interpretation of membrane proteins aided by machine learning algorithms.
Degree: PhD, Chemistry, 2018, Vanderbilt University
URL: http://hdl.handle.net/1803/11010 
► Helical membrane proteins (HMPs) play essential roles in various biological processes. Despite their prevalence in the genome, a very small portion (~2%) of structures in…
(more)
▼ Helical membrane proteins (HMPs) play essential roles in various biological processes. Despite their prevalence in the genome, a very small portion (~2%) of structures in the Protein Data Bank are HMPs, partially due to the experimental difficulties in determining structures of HMPs and their complexes. Therefore, accurate computational methods for predicting structure and interpreting variants of HMPs are particularly desirable.
We developed a method, using state-of-the-art machine learning techniques, that accurately predicts residue weighted contact numbers (WCNs) from amino acid sequences. We demonstrated that residues’ WCNs predicted by this method not only are effective restraints for improving the fraction of native contacts in tertiary structure prediction of HMPs, they can also be used to derive a powerful score for selecting native-like docking candidates of HMP complexes. We also developed a machine learning-based protein-specific method capable of accurately predicting functional consequences of variants of the KCNQ1 potassium channel.
The success of our methods suggests that using structural properties predicted by machine-learning algorithms as restraints can be an effective approach to improving sampling and scoring in membrane protein structure prediction. It also suggests a promising pipeline, where a machine learning model is tailored to a specific protein target and trained with a functionally validated data set to calibrate informatics tools.
Advisors/Committee Members: Terry Lybrand (committee member), Clare McCabe (committee member), Terunaga Nakagawa (committee member), Jens Meiler (Committee Chair).
Subjects/Keywords: machine learning; variant interpretation; membrane protein docking; protein structure prediction; protein folding
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APA (6th Edition):
Li, B. (2018). Structure prediction and variant interpretation of membrane proteins aided by machine learning algorithms. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/11010
Chicago Manual of Style (16th Edition):
Li, Bian. “Structure prediction and variant interpretation of membrane proteins aided by machine learning algorithms.” 2018. Doctoral Dissertation, Vanderbilt University. Accessed April 11, 2021.
http://hdl.handle.net/1803/11010.
MLA Handbook (7th Edition):
Li, Bian. “Structure prediction and variant interpretation of membrane proteins aided by machine learning algorithms.” 2018. Web. 11 Apr 2021.
Vancouver:
Li B. Structure prediction and variant interpretation of membrane proteins aided by machine learning algorithms. [Internet] [Doctoral dissertation]. Vanderbilt University; 2018. [cited 2021 Apr 11].
Available from: http://hdl.handle.net/1803/11010.
Council of Science Editors:
Li B. Structure prediction and variant interpretation of membrane proteins aided by machine learning algorithms. [Doctoral Dissertation]. Vanderbilt University; 2018. Available from: http://hdl.handle.net/1803/11010
Vanderbilt University
2.
Putnam, Daniel Kent.
BCL::SAXS - Small Angle X-Ray Scattering Profiles to Assist Protein Structure Prediction.
Degree: MS, Biomedical Informatics, 2013, Vanderbilt University
URL: http://hdl.handle.net/1803/10858
► The Biochemical Library (BCL) is a protein structure prediction algorithm developed in the Meiler Lab at Vanderbilt University based on the placement of secondary structure…
(more)
▼ The Biochemical Library (BCL) is a protein structure prediction algorithm developed in the Meiler Lab at
Vanderbilt University based on the placement of secondary structure elements. This algorithm can use experimental data such as nuclear magnetic resonance (NMR), Cryo-electron microscopy (CryoEM), and electron paramagnetic resonance (EPR), to assist in protein structure prediction but does not have the ability to use SAXS data. The first phase of my project was to add this capability to the BCL and create a SAXS compatibility score. GPU acceleration was used to parallelize the computations. The second phase of the project was to compute SAXS scores for protein models without side chain and loop region coordinate information, but preserve atom type information. Finally, the BCL::SAXS score was added to the minimization process in BCL::FOLD. The SAXS score can be used to filter erroneous initial protein models from further refinement, thus saving time and computation resources.
Advisors/Committee Members: Terry Lybrand (committee member), David Tabb (committee member), Jens Meiler (Committee Chair).
Subjects/Keywords: BCL::Fold; CRYSOL; de novo protein structure determination; Debye formula; GPU Acceleration; small angle X-ray scattering
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APA (6th Edition):
Putnam, D. K. (2013). BCL::SAXS - Small Angle X-Ray Scattering Profiles to Assist Protein Structure Prediction. (Thesis). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/10858
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Putnam, Daniel Kent. “BCL::SAXS - Small Angle X-Ray Scattering Profiles to Assist Protein Structure Prediction.” 2013. Thesis, Vanderbilt University. Accessed April 11, 2021.
http://hdl.handle.net/1803/10858.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Putnam, Daniel Kent. “BCL::SAXS - Small Angle X-Ray Scattering Profiles to Assist Protein Structure Prediction.” 2013. Web. 11 Apr 2021.
Vancouver:
Putnam DK. BCL::SAXS - Small Angle X-Ray Scattering Profiles to Assist Protein Structure Prediction. [Internet] [Thesis]. Vanderbilt University; 2013. [cited 2021 Apr 11].
Available from: http://hdl.handle.net/1803/10858.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Putnam DK. BCL::SAXS - Small Angle X-Ray Scattering Profiles to Assist Protein Structure Prediction. [Thesis]. Vanderbilt University; 2013. Available from: http://hdl.handle.net/1803/10858
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Vanderbilt University
3.
DeLuca, Samuel Louis.
Development of Novel Methods for Computational Protein Design and Protein-Ligand Docking.
Degree: PhD, Chemical and Physical Biology, 2015, Vanderbilt University
URL: http://hdl.handle.net/1803/12795
► The ability to make rapid predictions of macro-molecular structures will enable researchers to carry out effective protein design, virtual High Throughput Screening (vHTS) and rational…
(more)
▼ The ability to make rapid predictions of macro-molecular structures will enable researchers to carry out effective protein design, virtual High Throughput Screening (vHTS) and rational drug design studies. Here, we describe the development of several new methods in the service of these aims. Specifically, a novel energy term for protein design was implemented and optimized as part of the Rosetta molecular modeling suite. This energy term is based on a statistical analysis of experimental protein structural data, and aims to produce more native-like protein designs. Additionally, a new sampling algorithm and scoring function for the RosettaLigand protein-ligand docking tool was implemented. The new sampling algorithm results in a 30-fold increase in docking speed, and a 15% improvement in success rate across a wide range of protein systems. The new scoring function consists of a set of cartesian grids representing shape complementarity, hydrogen bonding, and ligand microenvironment environment properties. RosettaLigand docking predictions and scores were then combined with chemical descriptor information and used as the input to train a set of neural networks predicting ligand binding affinity. While the resulting networks did exhibit the ability to make predictions more effectively than RosettaLigand alone in a cross-validation study, the models were insufficiently general to make effective predictions when applied to a challenging, independent benchmarking set.
In addition to these new methods, appendix chapters detail the results of a ligand docking study into potential drug candidates targeting both RPA70 and MgluR5, an analysis of the limitations of the Rosetta atom typing system with respect to ligand parameterization, descriptions of a number of new software tools for the analysis of large protein datasets, and documentation of the protocols necessary to recapitulate the scientific studies reported here. In total, this work represents a substantial improvement in the overall performance of RosettaLigand, and provides numerous avenues for further research and development.
Advisors/Committee Members: Stephen Fesik (committee member), Heidi Hamm (committee member), Brian Bachmann (committee member), Terry Lybrand (Committee Chair).
Subjects/Keywords: RosettaScripts; RosettaDesign; protein design; machine learning; Docking; Protein-Ligand Docking; Rosetta
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APA (6th Edition):
DeLuca, S. L. (2015). Development of Novel Methods for Computational Protein Design and Protein-Ligand Docking. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/12795
Chicago Manual of Style (16th Edition):
DeLuca, Samuel Louis. “Development of Novel Methods for Computational Protein Design and Protein-Ligand Docking.” 2015. Doctoral Dissertation, Vanderbilt University. Accessed April 11, 2021.
http://hdl.handle.net/1803/12795.
MLA Handbook (7th Edition):
DeLuca, Samuel Louis. “Development of Novel Methods for Computational Protein Design and Protein-Ligand Docking.” 2015. Web. 11 Apr 2021.
Vancouver:
DeLuca SL. Development of Novel Methods for Computational Protein Design and Protein-Ligand Docking. [Internet] [Doctoral dissertation]. Vanderbilt University; 2015. [cited 2021 Apr 11].
Available from: http://hdl.handle.net/1803/12795.
Council of Science Editors:
DeLuca SL. Development of Novel Methods for Computational Protein Design and Protein-Ligand Docking. [Doctoral Dissertation]. Vanderbilt University; 2015. Available from: http://hdl.handle.net/1803/12795
Vanderbilt University
4.
Willcock, Thomas Charles.
Ligand Docking Benchmark in Rosetta using Explicitly Placed Atomic Orbitals.
Degree: MS, Chemistry, 2015, Vanderbilt University
URL: http://hdl.handle.net/1803/12998
► Protein-ligand interactions are important in a variety of biological areas. The strength and location of these interactions is driven by Partial Covalent Interactions between the…
(more)
▼ Protein-ligand interactions are important in a variety of biological areas. The strength and location of these interactions is driven by Partial Covalent Interactions between the protein and ligand. The Rosetta framework has been updated to explicitly capture and score these interactions. A ligand docking benchmark using this procedure performs between ten and fifteen percent better than the previous procedure performs. Explicit placement of atomic orbitals was used to capture the interactions. Orbitals were placed using hybridization information consistent with quantum chemical calculations performed on the same benchmark set. A statistical model over 8000 high resolution crystal structures was generated in order to score hydrogen bonding interactions, cation-pi interactions, and pi-pi interactions. In most cases, important binding interactions were captured.
Advisors/Committee Members: Terry Lybrand (committee member), Lidia Smentek (committee member), Jens Meiler (Committee Chair).
Subjects/Keywords: Ligand Docking; Rosetta; Score Functions; Proteins; Benchmark; Orbitals
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APA (6th Edition):
Willcock, T. C. (2015). Ligand Docking Benchmark in Rosetta using Explicitly Placed Atomic Orbitals. (Thesis). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/12998
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Willcock, Thomas Charles. “Ligand Docking Benchmark in Rosetta using Explicitly Placed Atomic Orbitals.” 2015. Thesis, Vanderbilt University. Accessed April 11, 2021.
http://hdl.handle.net/1803/12998.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Willcock, Thomas Charles. “Ligand Docking Benchmark in Rosetta using Explicitly Placed Atomic Orbitals.” 2015. Web. 11 Apr 2021.
Vancouver:
Willcock TC. Ligand Docking Benchmark in Rosetta using Explicitly Placed Atomic Orbitals. [Internet] [Thesis]. Vanderbilt University; 2015. [cited 2021 Apr 11].
Available from: http://hdl.handle.net/1803/12998.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Willcock TC. Ligand Docking Benchmark in Rosetta using Explicitly Placed Atomic Orbitals. [Thesis]. Vanderbilt University; 2015. Available from: http://hdl.handle.net/1803/12998
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Vanderbilt University
5.
DeLuca, Stephanie Judith Han Hirst.
Protein structure elucidation by combining computational and experimental methods.
Degree: PhD, Chemical and Physical Biology, 2015, Vanderbilt University
URL: http://hdl.handle.net/1803/10724
► Membrane proteins remain a particular challenge in structural biology. Only approximately 1.5% of reported tertiary structures and around 100 unique polytopic membrane proteins are represented…
(more)
▼ Membrane proteins remain a particular challenge in structural biology. Only approximately 1.5% of reported tertiary structures and around 100 unique polytopic membrane proteins are represented in the Protein Data Bank (PDB). Site-directed spin labeling electron paramagnetic resonance spectroscopy (SDSL-EPR) is often used for the structural characterization of proteins that elude other techniques, such as X-ray crystallography and NMR. RosettaEPR combines SDSL-EPR distance data with computational methods to improve high-resolution protein structure prediction. We demonstrated the feasibility of using RosettaEPR with soluble proteins by benchmarking the method on T4-lysozyme, for which a final model of 1.7Å accuracy was obtained. RosettaTMH, a new membrane protein de novo folding method that employs rigid body sampling, is also introduced. It expands upon RosettaEPR to cover the important class of membrane proteins. RosettaTMH was benchmarked on 34 membrane proteins of known structure using simulated EPR distance restraints. It was able to sample the correct topology for 33 of 34 proteins and improves Rosetta’s ability to predict the three-dimensional structure of large membrane proteins, such as transporters and receptors.
Advisors/Committee Members: Walter Chazin (committee member), Charles Sanders (committee member), Borden Lacy (committee member), Terry Lybrand (committee member), Albert Beth (Committee Chair).
Subjects/Keywords: Rosetta; membrane protein; modeling; GPCR; method development; hybrid techniques; experimental restraints; NMR; nuclear magnetic resonance; EPR; electron paramagnetic resonance; peptide
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APA ·
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APA (6th Edition):
DeLuca, S. J. H. H. (2015). Protein structure elucidation by combining computational and experimental methods. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/10724
Chicago Manual of Style (16th Edition):
DeLuca, Stephanie Judith Han Hirst. “Protein structure elucidation by combining computational and experimental methods.” 2015. Doctoral Dissertation, Vanderbilt University. Accessed April 11, 2021.
http://hdl.handle.net/1803/10724.
MLA Handbook (7th Edition):
DeLuca, Stephanie Judith Han Hirst. “Protein structure elucidation by combining computational and experimental methods.” 2015. Web. 11 Apr 2021.
Vancouver:
DeLuca SJHH. Protein structure elucidation by combining computational and experimental methods. [Internet] [Doctoral dissertation]. Vanderbilt University; 2015. [cited 2021 Apr 11].
Available from: http://hdl.handle.net/1803/10724.
Council of Science Editors:
DeLuca SJHH. Protein structure elucidation by combining computational and experimental methods. [Doctoral Dissertation]. Vanderbilt University; 2015. Available from: http://hdl.handle.net/1803/10724
Vanderbilt University
6.
Covington, Cody Lance.
Chiroptical Spectroscopic Studies on Surfactants, Other Aggregating Systems, and Natural Products.
Degree: PhD, Chemistry, 2016, Vanderbilt University
URL: http://hdl.handle.net/1803/11624
► Recent experimental studies have shown unexpected chiroptical response from some chiral surfactant molecules. In these cases, the magnitude of the specific optical rotation was seen…
(more)
▼ Recent experimental studies have shown unexpected chiroptical response from some chiral surfactant molecules. In these cases, the magnitude of the specific optical rotation was seen to change as a function of surfactant concentration, which is considered to be due to molecular aggregation and contrary to that known for typical organic molecules. To explain these experimental results on the +10,000 atom surfactant systems, non-traditional methods are necessary. To that end, a large number of molecular dynamics simulations, quantum mechanical calculations, and extensive analysis have been performed on a model system, the lauryl ester of phenylalanine. Monomer-dimer equilibrium, representing the simplest form of aggregation, and its influence on the Horeau effect, have also been investigated using pantolactone and 2-hydroxy-3-pinanone as test cases. Also a novel chiroptical spectral analysis method utilizing the Dissymmetry Factor (DF) spectrum has been developed. Studies ranging from rigid to flexible molecules have demonstrated the advantages of the DF method, especially when several diastereomers are involved. Using the DF spectrum as an additional means of analysis, the previously undetermined absolute configurations of four natural products have been determined.
Advisors/Committee Members: Timothy Hanusa (committee member), Terry Lybrand (committee member), Janet Macdonald (committee member), Kalman Varga (committee member), Prasad Polavarapu (Committee Chair).
Subjects/Keywords: chiroptical spectroscopy
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APA (6th Edition):
Covington, C. L. (2016). Chiroptical Spectroscopic Studies on Surfactants, Other Aggregating Systems, and Natural Products. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/11624
Chicago Manual of Style (16th Edition):
Covington, Cody Lance. “Chiroptical Spectroscopic Studies on Surfactants, Other Aggregating Systems, and Natural Products.” 2016. Doctoral Dissertation, Vanderbilt University. Accessed April 11, 2021.
http://hdl.handle.net/1803/11624.
MLA Handbook (7th Edition):
Covington, Cody Lance. “Chiroptical Spectroscopic Studies on Surfactants, Other Aggregating Systems, and Natural Products.” 2016. Web. 11 Apr 2021.
Vancouver:
Covington CL. Chiroptical Spectroscopic Studies on Surfactants, Other Aggregating Systems, and Natural Products. [Internet] [Doctoral dissertation]. Vanderbilt University; 2016. [cited 2021 Apr 11].
Available from: http://hdl.handle.net/1803/11624.
Council of Science Editors:
Covington CL. Chiroptical Spectroscopic Studies on Surfactants, Other Aggregating Systems, and Natural Products. [Doctoral Dissertation]. Vanderbilt University; 2016. Available from: http://hdl.handle.net/1803/11624
Vanderbilt University
7.
Heinze, Sten.
Improvements to BCL::Fold de novo Protein Structure Prediction.
Degree: PhD, Chemistry, 2015, Vanderbilt University
URL: http://hdl.handle.net/1803/12144
► Proteins play a pivotal role in the functions of a cell. Structural information about proteins facilitates the understanding of their function. Limitations of experimental methods…
(more)
▼ Proteins play a pivotal role in the functions of a cell. Structural information about proteins facilitates the understanding of their function. Limitations of experimental methods make it difficult to determine the structure experimentally for certain proteins. Structure prediction methods and other approaches to derive information from existing experimental data can aid in elucidating protein structure and guide further experiments. BCL::Align is a multiple sequence alignment tool using a dynamic programming algorithm. Its customizable scoring function is a weighted sum of different scoring terms that can be tailored for different applications. Optimal weights for sequence alignment and fold recognition were determined by a Monte Carlo optimization. In a comparison with other methods, BCL::Align ranked best in alignment accuracy with a Cline score of 22.90 for the SABmark Twilight Zone reference set. The de novo protein structure prediction method BCL::Fold was tested in the Critical Assessment of Structure Prediction (CASP) experiment. Of 18 proteins, BCL::Fold sampled the topology correctly for 11 respectively 12 proteins, measured by topology score > 0.8 respectively GDT_TS > 33%. Analysis of models at the different steps resulted in the identification of non-native conformations for loops and beta sheets. Filtering of models by the new loop angle scoring term enriched for native-like models. Small Angle X-ray scattering (SAXS) experiments provide low-resolution information about a protein’s shape. While insufficient to obtain an atomic resolution protein structure, it can be used in BCL::Fold to focus the sampling on models that agree with the SAXS data. Receiver operator characteristic (ROC) curve analysis resulted in an Area under the curve (AUC) of 0.9264 showing that topologies can be discriminated even for BCL models with a reduced representation. In a folding benchmark, using SAXS data improved models. Filtering models by agreement with SAXS data enriches for correct models; and building models with SAXS data yields models that are more native like.
Advisors/Committee Members: Andes Hess (committee member), Prasad Polavarapu (committee member), Terry Lybrand (committee member), Jarrod Smith (committee member), Jens Meiler (Committee Chair).
Subjects/Keywords: SABmark; Cline; BCL::Fold; CASP; Topology score; loop predictions; sheet alignment; SAXS; Debye; sequence analysis; BCL::Align; sequence alignment
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APA (6th Edition):
Heinze, S. (2015). Improvements to BCL::Fold de novo Protein Structure Prediction. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/12144
Chicago Manual of Style (16th Edition):
Heinze, Sten. “Improvements to BCL::Fold de novo Protein Structure Prediction.” 2015. Doctoral Dissertation, Vanderbilt University. Accessed April 11, 2021.
http://hdl.handle.net/1803/12144.
MLA Handbook (7th Edition):
Heinze, Sten. “Improvements to BCL::Fold de novo Protein Structure Prediction.” 2015. Web. 11 Apr 2021.
Vancouver:
Heinze S. Improvements to BCL::Fold de novo Protein Structure Prediction. [Internet] [Doctoral dissertation]. Vanderbilt University; 2015. [cited 2021 Apr 11].
Available from: http://hdl.handle.net/1803/12144.
Council of Science Editors:
Heinze S. Improvements to BCL::Fold de novo Protein Structure Prediction. [Doctoral Dissertation]. Vanderbilt University; 2015. Available from: http://hdl.handle.net/1803/12144
Vanderbilt University
8.
Fu, Darwin Yu.
Improving Protein-Small Molecule Structure Predictions with Ensemble Methods, or Using Computers to Guess How Tiny Things Fit Together.
Degree: PhD, Chemistry, 2018, Vanderbilt University
URL: http://hdl.handle.net/1803/13786
► Protein-small molecule structure prediction, or protein-ligand docking, is a computational method for modeling how binding partners will interaction on an atomic level. Accurate prediction of…
(more)
▼ Protein-small molecule structure prediction, or protein-ligand docking, is a computational method for modeling how binding partners will interaction on an atomic level. Accurate prediction of protein-small molecule interactions is an important step in the structure based drug discovery pipeline. Biological molecules are flexible and adopt different conformational shapes when binding with small molecules. Capturing this flexibility while maintaining computational efficiency is a critical challenge for docking software. This research developed novel methods within the Rosetta Macromolecular Modeling Suite to consider structural ensembles of proteins and small molecules during docking. The additional structural information is complemented with experimental structure-activity relationship data, which previously was only considered retroactively. The new ensemble docking methods was applied in collaboration to targets of pharmaceutical interest including metabotropic glutamate receptors, protease-activated receptors, and STAT proteins.
Advisors/Committee Members: Andes Hess, Ph.D. (committee member), Tony Capra, Ph.D. (committee member), Terry Lybrand, Ph.D. (committee member), Jens Meiler, Ph.D. (Committee Chair).
Subjects/Keywords: Rosetta; Protein-Ligand Docking; Molecular Modeling; Small Molecules; G-Protein Coupled Receptors; Protein Structure Prediction
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APA ·
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APA (6th Edition):
Fu, D. Y. (2018). Improving Protein-Small Molecule Structure Predictions with Ensemble Methods, or Using Computers to Guess How Tiny Things Fit Together. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/13786
Chicago Manual of Style (16th Edition):
Fu, Darwin Yu. “Improving Protein-Small Molecule Structure Predictions with Ensemble Methods, or Using Computers to Guess How Tiny Things Fit Together.” 2018. Doctoral Dissertation, Vanderbilt University. Accessed April 11, 2021.
http://hdl.handle.net/1803/13786.
MLA Handbook (7th Edition):
Fu, Darwin Yu. “Improving Protein-Small Molecule Structure Predictions with Ensemble Methods, or Using Computers to Guess How Tiny Things Fit Together.” 2018. Web. 11 Apr 2021.
Vancouver:
Fu DY. Improving Protein-Small Molecule Structure Predictions with Ensemble Methods, or Using Computers to Guess How Tiny Things Fit Together. [Internet] [Doctoral dissertation]. Vanderbilt University; 2018. [cited 2021 Apr 11].
Available from: http://hdl.handle.net/1803/13786.
Council of Science Editors:
Fu DY. Improving Protein-Small Molecule Structure Predictions with Ensemble Methods, or Using Computers to Guess How Tiny Things Fit Together. [Doctoral Dissertation]. Vanderbilt University; 2018. Available from: http://hdl.handle.net/1803/13786
Vanderbilt University
9.
Kothiwale, Sandeepkumar Kailas.
A novel knowledge based conformation sampling algorithm and applications in drug discovery.
Degree: PhD, Chemistry, 2016, Vanderbilt University
URL: http://hdl.handle.net/1803/13765
► Computational approaches have become important tools in drug discovery. Computational technologies have been developed for application in all aspects of the drug discovery process including…
(more)
▼ Computational approaches have become important tools in drug discovery. Computational technologies have been developed for application in all aspects of the drug discovery process including target identification, lead compound discovery, and lead compound optimization. Interactions of drugs with a protein targets depend on the ability to adopt a three-dimensional structure that is complementary. Complete and rapid prediction of conformational space is important for the success of computational drug discovery technologies. A novel knowledge based conformation sampling algorithm was implemented which derives a database of frequently sampled small molecule fragments within the Cambridge Structure Database and the Protein Data Bank. Likely fragment conformations or ‘rotamers’ are used for rapid sampling of molecular conformational space. The ‘rotamer’ approach has allowed integration of the algorithm into computational biology programs like ROSETTA and FOLDIT, the online science game. Computational methods like homology modelling, docking and virtual high throughput screening were applied in the discovery of novel inhibitors of Discoidin Domain Receptor kinase domain which led to the identification of at least two novel scaffolds.
Advisors/Committee Members: Dr. Ambra Pozzi (committee member), Dr. Terry Lybrand (committee member), Dr. Andes Hess (committee member), Dr. Jens Meiler (Committee Chair).
Subjects/Keywords: computational drug discovery; kinase selectivity; quantitative structure activity relationships; backpropagation algorithm; machine learning; knowledge-based; cheminformatics; conformational sampling; DDR1 kinase; neural networks; homology modelling
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APA ·
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APA (6th Edition):
Kothiwale, S. K. (2016). A novel knowledge based conformation sampling algorithm and applications in drug discovery. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/13765
Chicago Manual of Style (16th Edition):
Kothiwale, Sandeepkumar Kailas. “A novel knowledge based conformation sampling algorithm and applications in drug discovery.” 2016. Doctoral Dissertation, Vanderbilt University. Accessed April 11, 2021.
http://hdl.handle.net/1803/13765.
MLA Handbook (7th Edition):
Kothiwale, Sandeepkumar Kailas. “A novel knowledge based conformation sampling algorithm and applications in drug discovery.” 2016. Web. 11 Apr 2021.
Vancouver:
Kothiwale SK. A novel knowledge based conformation sampling algorithm and applications in drug discovery. [Internet] [Doctoral dissertation]. Vanderbilt University; 2016. [cited 2021 Apr 11].
Available from: http://hdl.handle.net/1803/13765.
Council of Science Editors:
Kothiwale SK. A novel knowledge based conformation sampling algorithm and applications in drug discovery. [Doctoral Dissertation]. Vanderbilt University; 2016. Available from: http://hdl.handle.net/1803/13765
Vanderbilt University
10.
Breland, Erin Jenness.
Dissecting the role of QseC in mediating QseBC-PmrAB signaling in uropathogenic Escherichia coli.
Degree: PhD, Pharmacology, 2017, Vanderbilt University
URL: http://hdl.handle.net/1803/15485
► Antibiotic resistance in bacteria is increasing globally. Urinary tract infections, which account for the majority of antibiotic prescriptions, are primarily caused by uropathogenic E. coli…
(more)
▼ Antibiotic resistance in bacteria is increasing globally. Urinary tract infections, which account for the majority of antibiotic prescriptions, are primarily caused by uropathogenic E. coli (UPEC). The latest report by the World Health Organization places carbapenem-resistant Enterobacteriaceae as the third most critical pathogens for which new therapies are required. In cases of carbapenem resistance, a last-resort class of antibiotics is colistin, for which bacteria can acquire resistance by modifying their cell wall. Typically these resistance factors are encoded on mobile elements that can be shared. However, the work here shows that transient antibiotic resistance may be intrinsic to the genome. In uropathogenic Escherichia coli, two signaling networks, polymyxin resistance A and B and quorum sensing E. coli B and C (PmrAB and QseBC respectively), interact to regulate physiological and virulence factors in response to environmental cues. These signaling networks are two-component systems that include a cognate membrane-embedded histidine kinase (sensor) and a cytoplasmic response regulator (responder). Signaling network cross-interactions are rarely reported. This work highlights the direct interaction between non-cognate partners PmrB and QseB. Additionally, the presence of PmrA and QseC are required for appropriate response to signal and the function of QseC as a reverse-phosphotransferase to regulate the level of activated QseB. This work not only reveals that all four components are necessary for normal response, but also that these four components interact in the presence of ferric iron to alter the outer membrane of uropathogenic E. coli and increase transient resistance to polymyxin B, a last line of defense drug. These data open up new avenues for targeting uropathogenic E. coli and identify new potential antimicrobial targets.
Advisors/Committee Members: Benjamin Spiller (committee member), Terry Lybrand (committee member), Eric Skaar (committee member), Maria Hadjifrangiskou (committee member), Tina Iverson (Committee Chair).
Subjects/Keywords: PmrAB; E. coli; UPEC; two-component signaling; QseBC; transient resistance
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APA (6th Edition):
Breland, E. J. (2017). Dissecting the role of QseC in mediating QseBC-PmrAB signaling in uropathogenic Escherichia coli. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/15485
Chicago Manual of Style (16th Edition):
Breland, Erin Jenness. “Dissecting the role of QseC in mediating QseBC-PmrAB signaling in uropathogenic Escherichia coli.” 2017. Doctoral Dissertation, Vanderbilt University. Accessed April 11, 2021.
http://hdl.handle.net/1803/15485.
MLA Handbook (7th Edition):
Breland, Erin Jenness. “Dissecting the role of QseC in mediating QseBC-PmrAB signaling in uropathogenic Escherichia coli.” 2017. Web. 11 Apr 2021.
Vancouver:
Breland EJ. Dissecting the role of QseC in mediating QseBC-PmrAB signaling in uropathogenic Escherichia coli. [Internet] [Doctoral dissertation]. Vanderbilt University; 2017. [cited 2021 Apr 11].
Available from: http://hdl.handle.net/1803/15485.
Council of Science Editors:
Breland EJ. Dissecting the role of QseC in mediating QseBC-PmrAB signaling in uropathogenic Escherichia coli. [Doctoral Dissertation]. Vanderbilt University; 2017. Available from: http://hdl.handle.net/1803/15485
Vanderbilt University
11.
Konkle, Mary Elizabeth.
Indomethacin-Amides As Molecular Scaffolds To Investigate The Structure and Function of Cyclooxygenases, Thromboxane Synthase, and Sterol 14-alpha Demethylase From Trypanosoma Cruzi.
Degree: PhD, Chemistry, 2008, Vanderbilt University
URL: http://hdl.handle.net/1803/14679
► Indomethacin (INDO) has been a commercially available non-steroidal anti-inflammatory drug since 1963. As such, INDO has well-defined toxicology and pharmacokinetics that allow it to serve…
(more)
▼ Indomethacin (INDO) has been a commercially available non-steroidal anti-inflammatory drug since 1963. As such, INDO has well-defined toxicology and pharmacokinetics that allow it to serve as a known molecular scaffold that can be subtly modified to explore the structure and function of multiple enzyme systems. Neutralization of the INDO scaffold by amidation affords an inhibitor that is selective for cyclooxygenase-2 (COX-2) over COX-1. By utilizing newly synthesized INDO-amides, we report that a second-shell residue, residue472, is a molecular determinant for this selectivity via its influence on dynamic motions of active site residue Glu524. Additionally, we report this residue is also a molecular determinant of the competency of a COX isoform to oxygenate
2-arachidonoyl glycerol (2-AG). As such, we have determined that a COX-1 (mouse), contrary to previous reports, can oxygenate the endocannabinoid 2-AG.
We also report the design and synthesis of dual inhibitors of thromboxane synthase (TXAS) and COX-2. We have conferred TXAS inhibition through the addition of an amide group containing alkyl linkers of varying lengths and various positional isomers of the pyridyl moiety. As such, we have improved upon the previously reported structure activity relationship of TXAS inhibitors which demanded the presence of a free carboxylate and only a 3-pyridyl moiety.
Lastly, we have used INDO-amides as inhibitors of sterol 14-ƒÑƒndemethylase (CYP51) from the parasite Trypanosoma cruzi (TC). Infection by TC causes Chagas disease in Latin American countries. With these compounds, have been able to retard parasite growth in cardiomyocytes.
Advisors/Committee Members: Dr. Richard Armstrong (committee member), Dr. Terry Lybrand (committee member), Dr. Jens Meiler (committee member), Dr. Lawrence Marnett (Committee Chair).
Subjects/Keywords: Indomethcin; prostaglandins; Chagas; thromboxanes; COX; kinetic; Chagas' disease – Treatment; Cyclooxygenases – Inhibitors; Trypanosoma cruzi
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APA (6th Edition):
Konkle, M. E. (2008). Indomethacin-Amides As Molecular Scaffolds To Investigate The Structure and Function of Cyclooxygenases, Thromboxane Synthase, and Sterol 14-alpha Demethylase From Trypanosoma Cruzi. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/14679
Chicago Manual of Style (16th Edition):
Konkle, Mary Elizabeth. “Indomethacin-Amides As Molecular Scaffolds To Investigate The Structure and Function of Cyclooxygenases, Thromboxane Synthase, and Sterol 14-alpha Demethylase From Trypanosoma Cruzi.” 2008. Doctoral Dissertation, Vanderbilt University. Accessed April 11, 2021.
http://hdl.handle.net/1803/14679.
MLA Handbook (7th Edition):
Konkle, Mary Elizabeth. “Indomethacin-Amides As Molecular Scaffolds To Investigate The Structure and Function of Cyclooxygenases, Thromboxane Synthase, and Sterol 14-alpha Demethylase From Trypanosoma Cruzi.” 2008. Web. 11 Apr 2021.
Vancouver:
Konkle ME. Indomethacin-Amides As Molecular Scaffolds To Investigate The Structure and Function of Cyclooxygenases, Thromboxane Synthase, and Sterol 14-alpha Demethylase From Trypanosoma Cruzi. [Internet] [Doctoral dissertation]. Vanderbilt University; 2008. [cited 2021 Apr 11].
Available from: http://hdl.handle.net/1803/14679.
Council of Science Editors:
Konkle ME. Indomethacin-Amides As Molecular Scaffolds To Investigate The Structure and Function of Cyclooxygenases, Thromboxane Synthase, and Sterol 14-alpha Demethylase From Trypanosoma Cruzi. [Doctoral Dissertation]. Vanderbilt University; 2008. Available from: http://hdl.handle.net/1803/14679
Vanderbilt University
12.
Cho, Young-Jin.
NMR studies of an α,β-unsaturated aldehyde-derived interstrand carbinolamine DNA cross-link in the 5´-CpG-3´ sequence.
Degree: PhD, Chemistry, 2006, Vanderbilt University
URL: http://hdl.handle.net/1803/11566
► The chemistry of acrolein and crotonaldehyde-derived propano-deoxyguanosine (γ-OH-PdG and α-CH3-γ-OH-PdG) adducts was monitored in the 5´-CpG-3´ sequence within a dodecamer duplex by NMR spectroscopy, in…
(more)
▼ The chemistry of acrolein and crotonaldehyde-derived propano-deoxyguanosine (γ-OH-PdG and α-CH
3-γ-OH-PdG) adducts was monitored in the 5´-CpG-3´ sequence within a dodecamer duplex by NMR spectroscopy, in situ, using a series of site-specific
13C- and
15N-edited experiments. One striking phenomenon was the formation of an interstrand DNA cross-link, predominantly a carbinolamine. The cross-link existed in equilibrium with the non-crosslinked aldehyde and its geminal diol hydrate. The ratio of aldehyde/diol increased at higher temperatures. The effects of the pH and complementary bases were examined. Molecular modeling suggested that the carbinolamine linkage should be capable of maintaining Watson-Crick hydrogen bonds at both of the tandem C•G base pairs. In contrast, dehydration of the carbinolamine cross-link to an imine (Schiff base) cross-link, or cyclization of the latter to form a pyrimidopurinone cross-link, was predicted to require disruption of Watson-Crick hydrogen bonds at one or both of the tandem cross-linked C•G base pairs. Structural study of the <i>S</i>-crotonaldehyde-derived dG adduct ring-opened species suggested its slow generation of a cross-link was due to the configuration of the methyl group. The fully reduced <i>R</i>- and <i>S</i>-crotonaldehyde-derived cross-link studies confirm that these cross-links can be accommodated in duplex DNA. The methyl stereochemistry also affects the thermodynamic stability of the reduced cross-links in duplex DNA. The results provide a rationale for the stability of interstrand cross-links formed by acrolein and crotonaldehyde and perhaps other α,β-unsaturated aldehydes. These sequence-specific carbinolamine cross-links are anticipated to interfere with DNA replication and contribute to acrolein- and crotonaldehyde-mediated genotoxicity.
Advisors/Committee Members: Dr. Charse Sanders (committee member), Dr. Terry Lybrand (committee member), Dr. Sandra J. Rosenthal (committee member), Dr. Carmelo J. Rizzo (committee member), Dr. Michael P. Stone (Committee Chair).
Subjects/Keywords: acrolein; NMR; interstrand DNA cross-link; carbinolamine; crotonaldehyde
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APA ·
Chicago ·
MLA ·
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CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Cho, Y. (2006). NMR studies of an α,β-unsaturated aldehyde-derived interstrand carbinolamine DNA cross-link in the 5´-CpG-3´ sequence. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/11566
Chicago Manual of Style (16th Edition):
Cho, Young-Jin. “NMR studies of an α,β-unsaturated aldehyde-derived interstrand carbinolamine DNA cross-link in the 5´-CpG-3´ sequence.” 2006. Doctoral Dissertation, Vanderbilt University. Accessed April 11, 2021.
http://hdl.handle.net/1803/11566.
MLA Handbook (7th Edition):
Cho, Young-Jin. “NMR studies of an α,β-unsaturated aldehyde-derived interstrand carbinolamine DNA cross-link in the 5´-CpG-3´ sequence.” 2006. Web. 11 Apr 2021.
Vancouver:
Cho Y. NMR studies of an α,β-unsaturated aldehyde-derived interstrand carbinolamine DNA cross-link in the 5´-CpG-3´ sequence. [Internet] [Doctoral dissertation]. Vanderbilt University; 2006. [cited 2021 Apr 11].
Available from: http://hdl.handle.net/1803/11566.
Council of Science Editors:
Cho Y. NMR studies of an α,β-unsaturated aldehyde-derived interstrand carbinolamine DNA cross-link in the 5´-CpG-3´ sequence. [Doctoral Dissertation]. Vanderbilt University; 2006. Available from: http://hdl.handle.net/1803/11566
Vanderbilt University
13.
Petrovic, Ana Grozdan.
Chiroptical spectroscopic structural determination of organic, inorganic and biomolecules.
Degree: PhD, Chemistry, 2007, Vanderbilt University
URL: http://hdl.handle.net/1803/13922
► The significance of being able to reliably establish the structure of chiral molecules is manifested through the recognition that different enantiomers and diastereomers of the…
(more)
▼ The significance of being able to reliably establish the structure of chiral molecules is manifested through the recognition that different enantiomers and diastereomers of the same compound can have vastly different effects with respect to a specific function. A portion of this Dissertation describes the configurational and conformational analysis of chiral molecules via experimental and theoretical applications of chiroptical spectroscopic methods. Three chiroptical spectroscopic techniques, Vibrational Circular Dichroism (VCD), Electronic Circular Dichroism (ECD), and Optical Rotatory Dispersion (ORD), complement each other in a quest for an unambiguous structural determination. A comparison between experimentally obtained and theoretically predicted chiroptical spectroscopic properties allows the stereochemical elucidation of chiral species. The first tandem application of the three methods has been demonstrated through structural investigations of several chiral organic and inorganic molecules: C2–symmetric spiroselenurane (Chapter 2), trinickel(II) complex of dypiridylamine (Chapter 3), 2,2'-diphenyl-[3,3'-biphenanthrene]-4,4'-diol (Chapter 4), a set of sulfoxide-containing chiral molecules (Chapter 5), and t-butyl-phenyl-phosphinoamidate (Chapter 6). Chapter 7 of the Dissertation evaluates the utility of ECD for the analysis of ORD in dimethyl tartrate using KK transform. The last three chapters of the Dissertation pertain to VCD based investigations on carbohydrates (Chapter 8), homopolynucleotides (Chapter 9), and tetrapeptide (Chapter 10). These chapters not only evaluate the applicability of the VCD method for elucidating the structures of these classes of biomolecules, but also introduce, film state measurements which, when applicable, can greatly aid the VCD-based structural analysis.
Advisors/Committee Members: Eva Harth (committee member), Terry Lybrand (committee member), Michael Stone (committee member), Carmelo Rizzo (committee member), Prasad L. Polavarapu (Committee Chair).
Subjects/Keywords: ORD; ECD; Stereochemical Assignment; Density Functional Theory; VCD; Vibrational Circular Dichroism; Optical Rotatory Dispersion
Record Details
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APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Petrovic, A. G. (2007). Chiroptical spectroscopic structural determination of organic, inorganic and biomolecules. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/13922
Chicago Manual of Style (16th Edition):
Petrovic, Ana Grozdan. “Chiroptical spectroscopic structural determination of organic, inorganic and biomolecules.” 2007. Doctoral Dissertation, Vanderbilt University. Accessed April 11, 2021.
http://hdl.handle.net/1803/13922.
MLA Handbook (7th Edition):
Petrovic, Ana Grozdan. “Chiroptical spectroscopic structural determination of organic, inorganic and biomolecules.” 2007. Web. 11 Apr 2021.
Vancouver:
Petrovic AG. Chiroptical spectroscopic structural determination of organic, inorganic and biomolecules. [Internet] [Doctoral dissertation]. Vanderbilt University; 2007. [cited 2021 Apr 11].
Available from: http://hdl.handle.net/1803/13922.
Council of Science Editors:
Petrovic AG. Chiroptical spectroscopic structural determination of organic, inorganic and biomolecules. [Doctoral Dissertation]. Vanderbilt University; 2007. Available from: http://hdl.handle.net/1803/13922
. 
Open Access Theses and Dissertations