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You searched for subject:(Energy landscape reconstruction). Showing records 1 – 2 of 2 total matches.

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Georgia Tech

1. Haider, Ahmad. Direct measurement of energy landscapes of intermolecular and interfacial interactions using atomic force microscopy.

Degree: PhD, Mechanical Engineering, 2016, Georgia Tech

Energy barriers encountered in intermolecular and interfacial interactions determine the kinetics and equilibrium outcome of a multitude of key physical, chemical, and biological processes. The free energy landscape, i.e. the strength and physical extent of interaction energies between molecules, dictates the specificity and affinity of biological interactions. Knowledge of the energy landscape is also essential to understand the direction of a chemical reaction, the relative stability of intermediate and final states, and the corresponding reaction mechanisms. Despite advances in measuring interaction forces, determining energy landscapes at nanometer dimensions remains a challenge. Computer simulations do provide a useful approach for estimating free energy landscapes but only to the limit of the accuracy of the model potentials and the integration of the equations of motion. Indirect experimental approaches such as dynamic force spectroscopy measurements also do not completely determine the shape or curvature of the energy landscape, nor can they detect the presence of intermediate metastable states. The emergence of ultrasensitive force detection techniques such as atomic force microscope (AFM) could prove invaluable in direct determination of energy landscapes since they combine excellent force and distance resolution with the ability to probe local interactions at nanoscale levels. In this thesis, we have developed a AFM based technique to directly measure the free energy landscape of biological and interfacial interactions. The technique applies the Brownian (thermal) fluctuations to vibrate a sensitive AFM microcantilever through the energy profile between the tip and surface. By recording subtle deviations from the harmonic cantilever vibrations, and applying Boltzmann transformation techniques, the energy landscape is reconstructed. These techniques have been applied to measure the binding energy landscapes of ligand-receptor interactions in a biotin-avidin system. Through the use of stochastic excitations, we have also extended the applicability of our methods in measuring energy landscapes of strongly adhesive interfacial interactions with steep energy gradients, such as those encountered in silicon nitride and mica interfaces. Advisors/Committee Members: Sulchek, Todd (advisor), Hesketh, Peter (committee member), Brand, Oliver (committee member), Bassiri-Gharb, Nazanin (committee member), Frazier, Albert (committee member).

Subjects/Keywords: Atomic force microscope; Energy landscape reconstruction

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APA (6th Edition):

Haider, A. (2016). Direct measurement of energy landscapes of intermolecular and interfacial interactions using atomic force microscopy. (Doctoral Dissertation). Georgia Tech. Retrieved from http://hdl.handle.net/1853/58585

Chicago Manual of Style (16th Edition):

Haider, Ahmad. “Direct measurement of energy landscapes of intermolecular and interfacial interactions using atomic force microscopy.” 2016. Doctoral Dissertation, Georgia Tech. Accessed June 17, 2019. http://hdl.handle.net/1853/58585.

MLA Handbook (7th Edition):

Haider, Ahmad. “Direct measurement of energy landscapes of intermolecular and interfacial interactions using atomic force microscopy.” 2016. Web. 17 Jun 2019.

Vancouver:

Haider A. Direct measurement of energy landscapes of intermolecular and interfacial interactions using atomic force microscopy. [Internet] [Doctoral dissertation]. Georgia Tech; 2016. [cited 2019 Jun 17]. Available from: http://hdl.handle.net/1853/58585.

Council of Science Editors:

Haider A. Direct measurement of energy landscapes of intermolecular and interfacial interactions using atomic force microscopy. [Doctoral Dissertation]. Georgia Tech; 2016. Available from: http://hdl.handle.net/1853/58585


University of Alberta

2. Yu, Hao. Single-molecule studies of prion protein folding and misfolding.

Degree: PhD, Department of Physics, 2013, University of Alberta

Protein folding involves a stochastic search through the configurational energy landscape towards the native structure. Although most proteins have evolved to fold efficiently into a unique native structure, misfolding (the formation of non-native structures) occurs frequently in vivo causing a wide range of diseases. The prion protein PrP has the unique ability to propagate an infectious disease without transmitting any genetic material, based instead on a misfolded conformation which can reproduce itself. The mechanism of prion misfolding and propagation remains unsettled, from details about the earliest stages of misfolding to the structure of the infectious state. Part of the difficulty in understanding the structural conversion arises from the complexity of the underlying energy landscape. Single-molecule methods provide a powerful tool for probing complex folding pathways as in protein misfolding, because they allow rare and transient events to be observed directly. We used custom-built high resolution optical tweezers to study PrP one molecule at a time. By measuring folding trajectories of single PrP molecules held under tension, we found that the native folding pathway involves only two states, without evidence for partially folded intermediates that have been proposed to mediate misfolding. The full energy profile was reconstructed for the native folding of PrP, revealing a double-well potential with an extended partially-unfolded transition state. Interestingly, three different misfolding pathways were detected, all starting from the unfolded state. A mutant PrP with higher aggregation propensity showed increased occupancy of some of the misfolded states, suggesting these states may act as intermediates during aggregation. To investigate the mechanism of PrP misfolding further, we characterized the folding pathways of PrP when two molecules interact to form a dimer. Remarkably, the dimer invariably formed a stable misfolded structure, via multiple partially-folded intermediates. We mapped the energy landscape for PrP dimer misfolding and identified a key intermediate that leads to misfolding by kinetically blocking the formation of the native structure. These results provide mechanistic insight into the formation of non-native structures of PrP and demonstrate a general platform for studying protein misfolding and aggregation at the single-molecule level, with wide applicability for understanding disease and biological function.

Subjects/Keywords: single molecule; protein misfolding; biophysics; RNA folding; force spectroscopy; prion disease; energy-landscape reconstruction; aggregation; transmissible spongiform encephalopathies; riboswitch; energy landscape; tandem dimer; protein folding; opitcal tweezers; kinetics; transition path time; prion protein

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

APA (6th Edition):

Yu, H. (2013). Single-molecule studies of prion protein folding and misfolding. (Doctoral Dissertation). University of Alberta. Retrieved from https://era.library.ualberta.ca/files/1g05fb884

Chicago Manual of Style (16th Edition):

Yu, Hao. “Single-molecule studies of prion protein folding and misfolding.” 2013. Doctoral Dissertation, University of Alberta. Accessed June 17, 2019. https://era.library.ualberta.ca/files/1g05fb884.

MLA Handbook (7th Edition):

Yu, Hao. “Single-molecule studies of prion protein folding and misfolding.” 2013. Web. 17 Jun 2019.

Vancouver:

Yu H. Single-molecule studies of prion protein folding and misfolding. [Internet] [Doctoral dissertation]. University of Alberta; 2013. [cited 2019 Jun 17]. Available from: https://era.library.ualberta.ca/files/1g05fb884.

Council of Science Editors:

Yu H. Single-molecule studies of prion protein folding and misfolding. [Doctoral Dissertation]. University of Alberta; 2013. Available from: https://era.library.ualberta.ca/files/1g05fb884

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