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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 ?-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.

SUBMITTER: Chen J

PROVIDER: S-EPMC6135771 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Atomistic Peptide Folding Simulations Reveal Interplay of Entropy and Long-Range Interactions in Folding Cooperativity.

Chen Jianlin J Liu Xiaorong X Chen Jianhan J

Scientific reports 20180912 1

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 ...[more]

PMID: 30209295

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Project description:Although molecular simulation methods have yielded valuable insights into mechanistic aspects of protein refolding in vitro, they have up to now not been used to model the folding of proteins as they are actually synthesized by the ribosome. To address this issue, we report here simulation studies of three model proteins: chymotrypsin inhibitor 2 (CI2), barnase, and Semliki forest virus protein (SFVP), and directly compare their folding during ribosome-mediated synthesis with their refolding from random, denatured conformations. To calibrate the methodology, simulations are first compared with in vitro data on the folding stabilities of N-terminal fragments of CI2 and barnase; the simulations reproduce the fact that both the stability and thermal folding cooperativity increase as fragments increase in length. Coupled simulations of synthesis and folding for the same two proteins are then described, showing that both fold essentially post-translationally, with mechanisms effectively identical to those for refolding. In both cases, confinement of the nascent polypeptide chain within the ribosome tunnel does not appear to promote significant formation of native structure during synthesis; there are however clear indications that the formation of structure within the nascent chain is sensitive to location within the ribosome tunnel, being subject to both gain and loss as the chain lengthens. Interestingly, simulations in which CI2 is artificially stabilized show a pronounced tendency to become trapped within the tunnel in partially folded conformations: non-cooperative folding, therefore, appears in the simulations to exert a detrimental effect on the rate at which fully folded conformations are formed. Finally, simulations of the two-domain protease module of SFVP, which experimentally folds cotranslationally, indicate that for multi-domain proteins, ribosome-mediated folding may follow different pathways from those taken during refolding. Taken together, these studies provide a first step toward developing more realistic methods for simulating protein folding as it occurs in vivo.

Dataset Information

Atomistic Peptide Folding Simulations Reveal Interplay of Entropy and Long-Range Interactions in Folding Cooperativity.

Publications

Atomistic Peptide Folding Simulations Reveal Interplay of Entropy and Long-Range Interactions in Folding Cooperativity.

Similar Datasets

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