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Predictive Sampling of Rare Conformational Events in Aqueous Solution

Title: Predictive Sampling of Rare Conformational Events in Aqueous Solution: Designing a Generalized Orthogonal Space Tempering Method.
Name(s): Lu, Chao, author
Li, Xubin, author
Wu, Dongsheng, author
Zheng, Lianqing, author
Yang, Wei, author
Type of Resource: text
Genre: Journal Article
Date Issued: 2016-01-12
Physical Form: computer
online resource
Extent: 1 online resource
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 promote molecular fluctuations to enhance sampling of essential conformational changes, a common strategy is to construct an expanded Hamiltonian through a series of Hamiltonian perturbations and thereby broaden the distribution of certain interactions of focus. Due to a lack of active sampling of configuration response to Hamiltonian transitions, it is challenging for common expanded Hamiltonian methods to robustly explore solvent mediated rare conformational events. The orthogonal space sampling (OSS) scheme, as exemplified by the orthogonal space random walk and orthogonal space tempering methods, provides a general framework for synchronous acceleration of slow configuration responses. To more effectively sample conformational transitions in aqueous solution, in this work, we devised a 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 (Ala10) 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 Ala10 folding/unfolding free energy surfaces. The gOST result reveals that solvent cooperative fluctuations play a pivotal role in Ala10 folding/unfolding transitions. In addition, our assessment analysis suggests that because essential conformational events are mainly driven by the compensating fluctuations of essential solute-solvent and solute-solute interactions, commonly employed "predictive" sampling methods are unlikely to be effective on this seemingly "simple" system. The gOST development presented in this paper illustrates how to employ the OSS scheme for physics-based sampling method designs.
Identifier: FSU_pmch_26636477 (IID), 10.1021/acs.jctc.5b00953 (DOI), PMC4968881 (PMCID), 26636477 (RID), 26636477 (EID)
Grant Number: R01 GM111886, R01GM111886
Publication Note: This NIH-funded author manuscript originally appeared in PubMed Central at
Subject(s): Alanine/chemistry
Molecular Dynamics Simulation
Protein Folding
Protein Unfolding
Persistent Link to This Record:
Owner Institution: FSU
Is Part Of: Journal of chemical theory and computation.
Issue: iss. 1, vol. 12

Choose the citation style.
Lu, C., Li, X., Wu, D., Zheng, L., & Yang, W. (2016). Predictive Sampling of Rare Conformational Events in Aqueous Solution: Designing a Generalized Orthogonal Space Tempering Method. Journal Of Chemical Theory And Computation. Retrieved from