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You searched for subject:(Transition path time). Showing records 1 – 2 of 2 total matches.

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University of Texas – Austin

1. Satija, Rohit. Understanding structural transitions and dynamics in biomolecules at a single molecule level.

Degree: PhD, Cell and Molecular Biology, 2020, University of Texas – Austin

Transition paths are fleeting events when a molecule crosses a barrier separating stable configurational basins. Recent advances in single molecule experiments, including optical tweezers-based force spectroscopy and FRET-based techniques, and data analysis methods have allowed detection of various statistical properties of transition paths. These observations have highlighted an important limitation in their current theoretical interpretation – a model of diffusive dynamics of the reaction coordinate along a one-dimensional free energy landscape is often unable to account for measurements of transition path time distributions in single molecule experiments. Here, we report similar observations in a long all-atom simulation of a small fast folding protein that exhibits multiple folding and unfolding transitions. Specifically, we discovered that the distribution of transition path times in this case is much broader than the prediction of the one-dimensional diffusion model. Moreover, direct analysis of the dynamics of the reaction coordinate in this simulation as well as in several other polypeptide simulations revealed that those dynamics are not diffusive, but subdiffusive. To explain these observations, we developed and tested several non-Markovian models, which include memory effects in the dynamics of the reaction coordinate in the form of time-dependent transport coefficients. We invented a novel technique, based on an overdamped generalized Langevin equation, to extract conformational memory directly from one-dimensional trajectories in single molecule experiments and simulations. Finally, we tested our theories on loop formation kinetics in intrinsically disordered proteins and found that, while mean first passage times to loop closure are well described by both one-dimensional diffusion and generalized Langevin equation, neither of them can capture long-time tails observed in distributions of transition path times in all-atom simulations. Advisors/Committee Members: Makarov, Dmitrii E. (advisor), Elber, Ron (committee member), Russell, Rick (committee member), Ren, Pengyu (committee member), Florin, Ernst L (committee member).

Subjects/Keywords: Theoretical chemical physics; Reaction dynamics; Kinetics; Transition path time; Single molecule force spectroscopy; FRET; Subdiffusion; Non-Markovian models; Memory kernel; Loop closure; Protein folding

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APA (6th Edition):

Satija, R. (2020). Understanding structural transitions and dynamics in biomolecules at a single molecule level. (Doctoral Dissertation). University of Texas – Austin. Retrieved from http://dx.doi.org/10.26153/tsw/9031

Chicago Manual of Style (16th Edition):

Satija, Rohit. “Understanding structural transitions and dynamics in biomolecules at a single molecule level.” 2020. Doctoral Dissertation, University of Texas – Austin. Accessed October 28, 2020. http://dx.doi.org/10.26153/tsw/9031.

MLA Handbook (7th Edition):

Satija, Rohit. “Understanding structural transitions and dynamics in biomolecules at a single molecule level.” 2020. Web. 28 Oct 2020.

Vancouver:

Satija R. Understanding structural transitions and dynamics in biomolecules at a single molecule level. [Internet] [Doctoral dissertation]. University of Texas – Austin; 2020. [cited 2020 Oct 28]. Available from: http://dx.doi.org/10.26153/tsw/9031.

Council of Science Editors:

Satija R. Understanding structural transitions and dynamics in biomolecules at a single molecule level. [Doctoral Dissertation]. University of Texas – Austin; 2020. Available from: http://dx.doi.org/10.26153/tsw/9031


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 October 28, 2020. https://era.library.ualberta.ca/files/1g05fb884.

MLA Handbook (7th Edition):

Yu, Hao. “Single-molecule studies of prion protein folding and misfolding.” 2013. Web. 28 Oct 2020.

Vancouver:

Yu H. Single-molecule studies of prion protein folding and misfolding. [Internet] [Doctoral dissertation]. University of Alberta; 2013. [cited 2020 Oct 28]. 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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