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Exact rotamer optimization for protein design

Gordon, D. Benjamin and Hom, Geoffrey K. and Mayo, Stephen L. and Pierce, Niles A. (2003) Exact rotamer optimization for protein design. Journal of Computational Chemistry, 24 (2). pp. 232-243. ISSN 0192-8651. doi:10.1002/jcc.10121.

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Computational methods play a central role in the rational design of novel proteins. The present work describes a new hybrid exact rotamer optimization (HERO) method that builds on previous dead-end elimination algorithms to yield dramatic performance enhancements. Measured on experimentally validated physical models, these improvements make it possible to perform previously intractable designs of entire protein core, surface, or boundary regions. Computational demonstrations include a full core design of the variable domains of the light and heavy chains of catalytic antibody 48G7 FAB with 74 residues and 10^(128) conformations, a full core/boundary design of the β1 domain of protein G with 25 residues and 10^(53) conformations, and a full surface design of the β1 domain of protein G with 27 residues and 10^(60) conformations. In addition, a full sequence design of the β1 domain of protein G is used to demonstrate the strong dependence of algorithm performance on the exact form of the potential function and the fidelity of the rotamer library. These results emphasize that search algorithm performance for protein design can only be meaningfully evaluated on physical models that have been subjected to experimental scrutiny. The new algorithm greatly facilitates ongoing efforts to engineer increasingly complex protein features.

Item Type:Article
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URLURL TypeDescription DOIArticle
Mayo, Stephen L.0000-0002-9785-5018
Pierce, Niles A.0000-0003-2367-4406
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Additional Information:© 2002 Wiley Periodicals, Inc. Received 16 December 2001; Accepted 18 March 2002. Article first published online: 19 Dec. 2002. Contract/grant sponsor: Helen G. and Arthur McCallum Foundation (D.B.G.). Contract/grant sponsor: NRSA; contract/grant number: 5T32-GM07616 (G.K.H.). Contract/grant sponsor: Howard Hughes Medical Institute (S.L.M.). Contract/grant sponsor: Burroughs-Wellcome Foundation (N.A.P.). Contract/grant sponsor: Caltech Initiative in Computational Molecular Biology (N.A.P.).
Funding AgencyGrant Number
Helen G. and Arthur McCallum FoundationUNSPECIFIED
NIH Predoctoral Fellowship5T32-GM07616
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Burroughs-Wellcome FoundationUNSPECIFIED
Caltech Initiative in Computational Molecular BiologyUNSPECIFIED
Subject Keywords:Protein Conformation; Computational Biology; Algorithms; Proteins; dead-end elimination; side-chain placement; protein design; combinatorial optimization; NP-hard
Issue or Number:2
Record Number:CaltechAUTHORS:20110913-173425474
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Official Citation:Gordon, D. B., Hom, G. K., Mayo, S. L. and Pierce, N. A. (2003), Exact rotamer optimization for protein design. Journal of Computational Chemistry, 24: 232–243. doi: 10.1002/jcc.10121
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:25331
Deposited By: Marie Ary
Deposited On:23 Sep 2011 23:02
Last Modified:09 Nov 2021 16:32

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