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      Insights from Coarse-Grained Gō Models for Protein Folding and Dynamics

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          Abstract

          Exploring the landscape of large scale conformational changes such as protein folding at atomistic detail poses a considerable computational challenge. Coarse-grained representations of the peptide chain have therefore been developed and over the last decade have proved extremely valuable. These include topology-based Gō models, which constitute a smooth and funnel-like approximation to the folding landscape. We review the many variations of the Gō model that have been employed to yield insight into folding mechanisms. Their success has been interpreted as a consequence of the dominant role of the native topology in folding. The role of local contact density in determining protein dynamics is also discussed and is used to explain the ability of Gō-like models to capture sequence effects in folding and elucidate conformational transitions.

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          Residue-residue potentials with a favorable contact pair term and an unfavorable high packing density term, for simulation and threading.

          S Miyazawa, R L Jernigan (1996)
          Attractive inter-residue contact energies for proteins have been re-evaluated with the same assumptions and approximations used originally by us in 1985, but with a significantly larger set of protein crystal structures. An additional repulsive packing energy term, operative at higher densities to prevent overpacking, has also been estimated for all 20 amino acids as a function of the number of contacting residues, based on their observed distributions. The two terms of opposite sign are intended to be used together to provide an estimate of the overall energies of inter-residue interactions in simplified proteins without atomic details. To overcome the problem of how to utilize the many homologous proteins in the Protein Data Bank, a new scheme has been devised to assign different weights to each protein, based on similarities among amino acid sequences. A total of 1168 protein structures containing 1661 subunit sequences are actually used here. After the sequence weights have been applied, these correspond to an effective number of residue-residue contacts of 113,914, or about six times more than were used in the old analysis. Remarkably, the new attractive contact energies are nearly identical to the old ones, except for those with Leu and the rarer amino acids Trp and Met. The largest change found for Leu is surprising. The estimates of hydrophobicity from the contact energies for non-polar side-chains agree well with the experimental values. In an application of these contact energies, the sequences of 88 structurally distinct proteins in the Protein Data Bank are threaded at all possible positions without gaps into 189 different folds of proteins whose sequences differ from each other by at least 35% sequence identity. The native structures for 73 of 88 proteins, excluding 15 exceptional proteins such as membrane proteins, are all demonstrated to have the lowest alignment energies.
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            The protein folding problem.

            Ken Dill, S. Banu Ozkan, M Shell … (2008)
            The "protein folding problem" consists of three closely related puzzles: (a) What is the folding code? (b) What is the folding mechanism? (c) Can we predict the native structure of a protein from its amino acid sequence? Once regarded as a grand challenge, protein folding has seen great progress in recent years. Now, foldable proteins and nonbiological polymers are being designed routinely and moving toward successful applications. The structures of small proteins are now often well predicted by computer methods. And, there is now a testable explanation for how a protein can fold so quickly: A protein solves its large global optimization problem as a series of smaller local optimization problems, growing and assembling the native structure from peptide fragments, local structures first.
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              Topological and energetic factors: what determines the structural details of the transition state ensemble and "en-route" intermediates for protein folding? An investigation for small globular proteins.

              C Clementi, H Nymeyer, J. N. Onuchic (2000)
              Recent experimental results suggest that the native fold, or topology, plays a primary role in determining the structure of the transition state ensemble, at least for small, fast-folding proteins. To investigate the extent of the topological control of the folding process, we studied the folding of simplified models of five small globular proteins constructed using a Go-like potential to retain the information about the native structures but drastically reduce the energetic frustration and energetic heterogeneity among residue-residue native interactions. By comparing the structure of the transition state ensemble (experimentally determined by Phi-values) and of the intermediates with those obtained using our models, we show that these energetically unfrustrated models can reproduce the global experimentally known features of the transition state ensembles and "en-route" intermediates, at least for the analyzed proteins. This result clearly indicates that, as long as the protein sequence is sufficiently minimally frustrated, topology plays a central role in determining the folding mechanism. Copyright 2000 Academic Press.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Int J Mol Sci
                Journal ID (publisher-id): ijms
                Title: International Journal of Molecular Sciences
                Publisher: Molecular Diversity Preservation International (MDPI)
                ISSN (Electronic): 1422-0067
                Publication date Collection: March 2009
                Publication date (Electronic): 2 March 2009
                Volume: 10
                Issue: 3
                Pages: 889-905
                Affiliations
                [1 ] Department of Molecular Biology and Kellogg School of Science and Technology, The Scripps Research Institute, 10550 N. Torrey Pines Rd. TPC6 La Jolla, CA 92037, USA
                [2 ] Department of Chemistry and Biophysics Program, University of Michigan, 930 N. University Ave, Ann Arbor, MI 48109, USA
                Author notes
                [* ]Author to whom correspondence should be addressed; E-Mail: brookscl@ 123456umich.edu ; Tel. +1-734-647-6682; Fax: +1-734-647-1604
                Article
                Publisher ID: ijms-10-00889
                DOI: 10.3390/ijms10030889
                PMC ID: 2672008
                PubMed ID: 19399227
                SO-VID: 1e19438b-957e-438c-b512-469cfcacf595
                Copyright © © 2009 by the authors; licensee Molecular Diversity Preservation International, Basel, Switzerland. This article is an open-access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/3.0/).
                License:

                This article is an open-access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/3.0/).

                History
                Date received : 22 January 2009
                Date revision received : 23 February 2009
                Date accepted : 26 February 2009
                Categories
                Subject: Review

                ScienceOpen disciplines: Molecular biology
                Keywords: protein folding,conformational transitions,gō models,energy landscape,coarse-graining
                Data availability:
                ScienceOpen disciplines: Molecular biology
                Keywords: protein folding, conformational transitions, gō models, energy landscape, coarse-graining

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