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The topomer-sampling model of protein folding

Debe, Derek A. and Carlson, Matt J. and Goddard, William A., III (1999) The topomer-sampling model of protein folding. Proceedings of the National Academy of Sciences of the United States of America, 96 (6). pp. 2596-2601. ISSN 0027-8424. PMCID PMC15813. doi:10.1073/pnas.96.6.2596.

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Clearly, a protein cannot sample all of its conformations (e.g., ≈3^(100) ≈ 10^(48) for a 100 residue protein) on an in vivo folding timescale (<1 s). To investigate how the conformational dynamics of a protein can accommodate subsecond folding time scales, we introduce the concept of the native topomer, which is the set of all structures similar to the native structure (obtainable from the native structure through local backbone coordinate transformations that do not disrupt the covalent bonding of the peptide backbone). We have developed a computational procedure for estimating the number of distinct topomers required to span all conformations (compact and semicompact) for a polypeptide of a given length. For 100 residues, we find ≈3 × 10^7 distinct topomers. Based on the distance calculated between different topomers, we estimate that a 100-residue polypeptide diffusively samples one topomer every ≈3 ns. Hence, a 100-residue protein can find its native topomer by random sampling in just ≈100 ms. These results suggest that subsecond folding of modest-sized, single-domain proteins can be accomplished by a two-stage process of (i) topomer diffusion: random, diffusive sampling of the 3 × 10^7 distinct topomers to find the native topomer (≈0.1 s), followed by (ii) intratopomer ordering: nonrandom, local conformational rearrangements within the native topomer to settle into the precise native state.

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Goddard, William A., III0000-0003-0097-5716
Additional Information:© 1999 National Academy of Sciences. Contributed by William A. Goddard III, December 30, 1998. We thank Prof. Sunney I. Chan, Prof. Kevin W. Plaxco, and Dr. Jiro Sadanobu for helpful discussions and Lisa Plaxco for advice on the statistical analysis. We also thank Prof. Larry Smarr of National Center for Supercomputing Applications (University of Illinois, Urbana) for making possible the computational resources. This research was supported by the Department of Energy (BCTR DE-FG36-93CH10581) and National Science Foundation (CHE 95-22179 and ASC 9217368). The facilities of the Molecular Simulation Center are also supported by grants from Defense University Research Instrumentation Program/Army Research Office, British Petrolium Chemical, Army Research Office/Multidisciplinary University Research Initiative, Exxon, Seiko-Epson, Beckman Institute, Owens-Corning, Avery Dennison, Dow Chemical, National Science Foundation–National Partnership for Advanced Computational Infrastructure (University of California at San Diego), Chevron Petroleum Technology Co., Chevron Chemical Co., Asahi Chemical, and Chevron Research and Technology. The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked ‘‘advertisement’’ in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Funding AgencyGrant Number
Department of Energy (DOE)BCTR DE-FG36-93CH10581
NSFCHE 95-22179
NSFASC 9217368
Army Research Office (ARO)UNSPECIFIED
British Petroleum ChemicalUNSPECIFIED
Caltech Beckman InstituteUNSPECIFIED
National Partnership for Advanced Computational InfrastructureUNSPECIFIED
Chevron Petroleum Technology Co.UNSPECIFIED
Chevron Chemical Co.UNSPECIFIED
Chevron Research and TechnologyUNSPECIFIED
Issue or Number:6
PubMed Central ID:PMC15813
Record Number:CaltechAUTHORS:20141125-144835029
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Official Citation:Derek A. Debe, Matt J. Carlson, and William A. Goddard III The topomer-sampling model of protein folding PNAS 1999 96 (6) 2596-2601; doi:10.1073/pnas.96.6.2596
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:52158
Deposited By: Tony Diaz
Deposited On:26 Nov 2014 19:31
Last Modified:10 Nov 2021 19:21

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