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Computational simulation of biomolecules can provide important insights into protein design, protein-ligand binding interactions, and ab initio biomolecular folding, among other applications. Accurate treatment of the solvent environment is essential in such applications, but the use of explicit solvents can add considerable cost. Implicit treatment of solvent effects using a dielectric continuum model is an attractive alternative to explicit solvation since it is able to describe solvation effects without the inclusion of solvent degrees of freedom. Previously, we described the development and parameterization of implicit solvent models for small molecules. Here, we extend the parameterization of the generalized Kirkwood (GK) implicit solvent model for use with biomolecules described by the AMOEBA force field via the addition of corrections to the calculation of effective radii that account for interstitial spaces that arise within biomolecules. These include element-specific pairwise descreening scale factors, a short-range neck contribution to describe the solvent-excluded space between pairs of nearby atoms, and finally tanh-based rescaling of the overall descreening integral. We then apply the AMOEBA/GK implicit solvent to a set of ten proteins and achieve an average coordinate root mean square deviation for the experimental structures of 2.0 Å across 500 ns simulations. Overall, the continued development of implicit solvent models will help facilitate the simulation of biomolecules on mechanistically relevant timescales.
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Atomistic Peptide Folding Simulations Reveal Interplay of Entropy and Long-Range Interactions in Folding Cooperativity
Abstract Understanding how proteins fold has remained a problem of great interest in biophysical research. Atomistic computer simulations using physics-based force fields can provide important insights on the interplay of different interactions and energetics and their roles in governing the folding thermodynamics and mechanism. In particular, generalized Born (GB)-based implicit solvent force fields can be optimized to provide an appropriate balance between solvation and intramolecular interactions and successfully recapitulate experimental conformational equilibria for a set of helical and β-hairpin peptides. Here, we further demonstrate that key thermodynamic properties and their temperature dependence obtained from replica exchange molecular dynamics simulations of these peptides are in quantitative agreement with experimental results. Useful lessons can be learned on how the interplay of entropy and sequentially long-range interactions governs the mechanism and cooperativity of folding. These results highlight the great potential of high-quality implicit solvent force fields for studying protein folding and large-scale conformational transitions.
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- Award ID(s):
- 1817332
- PAR ID:
- 10153714
- Publisher / Repository:
- Nature Publishing Group
- Date Published:
- Journal Name:
- Scientific Reports
- Volume:
- 8
- Issue:
- 1
- ISSN:
- 2045-2322
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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