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Predictive Sampling of Protein Conformational Changes

Title: Predictive Sampling of Protein Conformational Changes.
Name(s): Li, Xubin, author
Yang, Wei, professor directing dissertation
Taylor, Kenneth A., university representative
Steinbock, Oliver, committee member
Li, Hong, committee member
Cross, Timothy A., committee member
Florida State University, degree granting institution
College of Arts and Sciences, degree granting college
Department of Chemistry and Biochemistry, degree granting department
Type of Resource: text
Genre: Text
Issuance: monographic
Date Issued: 2016
Publisher: Florida State University
Place of Publication: Tallahassee, Florida
Physical Form: computer
online resource
Extent: 1 online resource (136 pages)
Language(s): English
Abstract/Description: In aqueous solution, solute conformational transitions are governed by intimate interplays of the fluctuations of solute–solute, solute–water, and water–water interactions. To more effectively sample conformational transitions in aqueous solution, we devised a predictive sampling method: the generalized orthogonal space tempering (gOST) algorithm. Specifically, in the Hamiltonian perturbation part, a solvent-accessible-surface-area-dependent term is introduced to implicitly perturb near-solute water–water fluctuations; more importantly in the orthogonal space response part, the generalized force order parameter is generalized as a two-dimension order parameter set, in which essential solute–solvent and solute–solute components are separately treated. The gOST algorithm is evaluated through a molecular dynamics simulation study on the explicitly solvated deca-alanine peptide. On the basis of a fully automated sampling protocol, the gOST simulation enabled repetitive folding and unfolding of the solvated peptide within a single continuous trajectory and allowed for detailed constructions of deca-alanine folding/unfolding free energy surfaces. In addition, by employing the gOST method we enabled efficient molecular dynamics simulation of repetitive breaking and reforming of salt bridge structures within a minimalist salt-bridge model, the Asp-Arg dipeptide and thereby were able to map its detailed free energy landscape in aqueous solution. Our results reveal the critical role of local solvent structures in modulating salt-bridge partner interactions and imply the importance of water fluctuations on conformational dynamics that involves solvent accessible salt bridge formations. Based on the gOST method, we have developed a solvation force orthogonal space tempering (SFOST) algorithm, in which several major changes were made from the original gOST method. Due to compensating fluctuations of essential solute-solvent and solute-solute interactions, only essential solute-solvent interactions are perturbed in the SFOST algorithm. Importantly, the above treatment enabled us to incorporate a high order orthogonal space sampling strategy. Specifically, to enlarge fluctuations of essential solute-solvent interactions, a third order treatment was introduced to accelerate the coupled responses caused by fluctuations of essential solute-solvent interactions, which come from synchronous fluctuations of essential solute-solute interactions and solvent-solvent interactions. The SFOST algorithm was evaluated through a molecular dynamics simulation study on the explicitly solvated deca-alanine peptide. More importantly, the SFOST simulation explicitly revealed the compensating fluctuations between the essential solute-solvent interactions and the solvent-solvent interactions, suggesting that solvent cooperative fluctuations intimately interplay with deca-alanine conformational transitions. In addition, the SFOST algorithm was also employed to study ion conduction through gramicidin A (gA). By enlarging fluctuations of the ion-environment interactions, the SFOST simulation enabled several round trips of ion permeation through the channel and allowed detailed construction of free energy surfaces along the conduction. The calculated observables agree very well with experiment. We also found that fluctuations of channel orientations play an essential role in ion conduction. Furthermore, by employing the SFOST algorithm we enabled predictive sampling of the conformational ensemble of the p53 transcriptional activation domain 1 (TAD1). Strikingly, a helical structure resembling the MDM2-bound form was found in our SFOST simulation, indicating the pre-existing nature of the structure. Detailed studies of free energy surfaces revealed that the most popular state is not a fully disordered form but a partially helical state. Upon binding to MDM2, the hydrophobic interactions at the interface shift the conformational equilibrium to favor the total helical structure. In addition to the predictive sampling methods, we developed a Gaussian kernel Monte Carlo (GKMC) method to smoothly approximate multidimensional free energy surfaces of biomolecular processes. By taking a discrete probability distribution of sampled collective variables as an input, a biased Monte Carlo simulation is performed to efficiently resample the distribution in the collective variable space, leading to a smooth analytical estimate of the free energy surface. The GKMC method is evaluated by resampling data of a generalized orthogonal space tempering simulation of deca-alanine peptide, aiming to construct smooth one-dimensional and two-dimensional free energy surfaces along certain collective variables. As demonstrated in these model studies, the GKMC method can robustly construct smooth multidimensional free energy surfaces with super resolutions, which preserve probability distributions of target molecular processes. Constructing smooth free energy surfaces plays a vital role in interpreting simulation data to understand molecular processes of interest.
Identifier: FSU_FA2016_Li_fsu_0071E_13616 (IID)
Submitted Note: A Dissertation submitted to the Department of Chemistry and Biochemistry in partial fulfillment of the Doctor of Philosophy.
Degree Awarded: Fall Semester 2016.
Date of Defense: November 22, 2016.
Keywords: Orthogonal Space Tempering, Predictive Sampling, Protein Dynamics, Solvation Force
Bibliography Note: Includes bibliographical references.
Advisory Committee: Wei Yang, Professor Directing Dissertation; Kenneth A. Taylor, University Representative; Oliver Steinbock, Committee Member; Hong Li, Committee Member; Timothy A. Cross, Committee Member.
Subject(s): Chemistry, Physical and theoretical
Persistent Link to This Record:
Host Institution: FSU

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Li, X. (2016). Predictive Sampling of Protein Conformational Changes. Retrieved from