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Analysis of the Free-Energy Surface of Proteins from Reversible Folding Simulations

Allen, L.R., Krivov, S.V., Paci, E. and Dokholyan, N.V. (2009) Analysis of the Free-Energy Surface of Proteins from Reversible Folding Simulations. PLoS Computational Biology, 5 (7). e1000428. ISSN 1553-7358

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Abstract

Computer generated trajectories can, in principle, reveal the folding pathways of a protein at atomic resolution and possibly suggest general and simple rules for predicting the folded structure of a given sequence. While such reversible folding trajectories can only be determined ab initio using all-atom transferable force-fields for a few small proteins, they can be determined for a large number of proteins using coarse-grained and structure-based force-fields, in which a known folded structure is by construction the absolute energy and free-energy minimum. Here we use a model of the fast folding helical λ-repressor protein to generate trajectories in which native and non-native states are in equilibrium and transitions are accurately sampled. Yet, representation of the free-energy surface, which underlies the thermodynamic and dynamic properties of the protein model, from such a trajectory remains a challenge. Projections over one or a small number of arbitrarily chosen progress variables often hide the most important features of such surfaces. The results unequivocally show that an unprojected representation of the free-energy surface provides important and unbiased information and allows a simple and meaningful description of many-dimensional, heterogeneous trajectories, providing new insight into the possible mechanisms of fast-folding proteins.

Item Type: Article
Copyright, Publisher and Additional Information: © 2009 Allen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Institution: The University of Leeds
Academic Units: The University of Leeds > Faculty of Maths and Physical Sciences (Leeds) > School of Physics and Astronomy (Leeds)
Depositing User: Sherpa Assistant
Date Deposited: 09 Nov 2009 10:20
Last Modified: 15 Sep 2014 04:09
Published Version: http://dx.doi.org/10.1371/journal.pcbi.1000428
Status: Published
Publisher: Public Library of Science
Identification Number: doi: 10.1371/journal.pcbi.1000428
URI: http://eprints.whiterose.ac.uk/id/eprint/10092

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