Folding free-energy landscape of villin headpiece subdomain from molecular dynamics simulations.

Full Abstract

High-accuracy ab initio folding has remained an elusive objective despite decades of effort. To explore the folding landscape of villin headpiece subdomain HP35, we conducted two sets of replica exchange molecular dynamics for 200 ns each and three sets of conventional microsecond-long molecular dynamics simulations, using AMBER FF03 force field and a generalized-Born solvation model. The protein folded consistently to the native state; the lowest C(alpha)-rmsd from the x-ray structure was 0.46 A, and the C(alpha)- rmsd of the center of the most populated cluster was 1.78 A at 300 K. ab initio simulations have previously not reached this level. The folding landscape of HP35 can be partitioned into the native, denatured, and two intermediate-state regions. The native state is separated from the major folding intermediate state by a small barrier, whereas a large barrier exists between the major folding intermediate and the denatured states. The melting temperature T(m) = 339 K extracted from the heat-capacity profile was in close agreement with the experimentally derived T(m) = 342 K. A comprehensive picture of the kinetics and thermodynamics of HP35 folding emerges when the results from replica exchange and conventional molecular dynamics simulations are combined.

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Author information

Author/s: Lei, Hongxing (H); Wu, Chun (C); Liu, Haiguang (H); Duan, Yong (Y);

Affiliation: Genome Center and Department of Applied Science, University of California, Davis, CA 95616, USA.

Grants: GM64458 (Agency:NIGMS NIH HHS) ; GM67168 (Agency:NIGMS NIH HHS)

Journal and publication information

Publication Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.

Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A), published in United States. (Language: eng)

Reference: 2007-Mar; vol 104 (issue 12) : pp 4925-30

Dates: Created 2007/03/21; Completed 2007/04/30; Revised 2008/11/20;

PMID: 17360390, status: MEDLINE (last retrieval date: 12/26/2008)

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Cluster Analysis
Computer Simulation
Models, Molecular
Neurofilament Proteins - chemistry; metabolism
Peptide Fragments - chemistry; metabolism
Principal Component Analysis

Associated Chemicals: Neurofilament Proteins (0) ; Peptide Fragments (0) ; villin headpiece subdomain peptide (0)

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