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A Bayes-inspired theory for optimally building an efficient coarse-grained folding force field.

ABSTRACT: Because of their potential utility in predicting conformational changes and assessing folding dynamics, coarse-grained (CG) RNA folding models are appealing for rapid characterization of RNA molecules. Previously, we reported the iterative simulated RNA reference state (IsRNA) method for parameterizing a CG force field for RNA folding, which consecutively updates the simulation force field to reflect marginal distributions of folding coordinates in the structure database and extract various energy terms. While the IsRNA model was validated by showing close agreement between the IsRNA-simulated and experimentally observed distributions, here, we expand our theoretical understanding of the model and, in doing so, improve the parameterization process to optimize the subset of included folding coordinates, which leads to accelerated simulations. Using statistical mechanical theory, we analyze the underlying, Bayesian concept that drives parameterization of the energy function, providing a general method for developing predictive, knowledge-based, polymer force fields on the basis of limited data. Furthermore, we propose an optimal parameterization procedure, based on the principal of maximum entropy.

SUBMITTER: Hurst T

PROVIDER: S-EPMC8336718 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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A Bayes-inspired theory for optimally building an efficient coarse-grained folding force field.

Hurst Travis T Zhang Dong D Zhou Yuanzhe Y Chen Shi-Jie SJ

Communications in information and systems 20210101 1

Because of their potential utility in predicting conformational changes and assessing folding dynamics, coarse-grained (CG) RNA folding models are appealing for rapid characterization of RNA molecules. Previously, we reported the iterative simulated RNA reference state (IsRNA) method for parameterizing a CG force field for RNA folding, which consecutively updates the simulation force field to reflect marginal distributions of folding coordinates in the structure database and extract various ener ...[more]

PMID: 34354546

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Project description:Coarse-grained molecular dynamics simulations offer a dramatic extension of the time-scale of simulations compared to all-atom approaches. In this article, we describe the use of the physics-based united-residue (UNRES) force field, developed in our laboratory, in protein-structure simulations. We demonstrate that this force field offers about a 4000-times extension of the simulation time scale; this feature arises both from averaging out the fast-moving degrees of freedom and reduction of the cost of energy and force calculations compared to all-atom approaches with explicit solvent. With massively parallel computers, microsecond folding simulation times of proteins containing about 1000 residues can be obtained in days. A straightforward application of canonical UNRES/MD simulations, demonstrated with the example of the N-terminal part of the B-domain of staphylococcal protein A (PDB code: 1BDD, a three-alpha-helix bundle), discerns the folding mechanism and determines kinetic parameters by parallel simulations of several hundred or more trajectories. Use of generalized-ensemble techniques, of which the multiplexed replica exchange method proved to be the most effective, enables us to compute thermodynamics of folding and carry out fully physics-based prediction of protein structure, in which the predicted structure is determined as a mean over the most populated ensemble below the folding-transition temperature. By using principal component analysis of the UNRES folding trajectories of the formin-binding protein WW domain (PDB code: 1E0L; a three-stranded antiparallel beta-sheet) and 1BDD, we identified representative structures along the folding pathways and demonstrated that only a few (low-indexed) principal components can capture the main structural features of a protein-folding trajectory; the potentials of mean force calculated along these essential modes exhibit multiple minima, as opposed to those along the remaining modes that are unimodal. In addition, a comparison between the structures that are representative of the minima in the free-energy profile along the essential collective coordinates of protein folding (computed by principal component analysis) and the free-energy profile projected along the virtual-bond dihedral angles gamma of the backbone revealed the key residues involved in the transitions between the different basins of the folding free-energy profile, in agreement with existing experimental data for 1E0L .

Dataset Information

A Bayes-inspired theory for optimally building an efficient coarse-grained folding force field.

Publications

A Bayes-inspired theory for optimally building an efficient coarse-grained folding force field.

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