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Thermodynamic prediction of protein neutrality

Bloom, Jesse D. and Silberg, Jonathan J. and Wilke, Claus O. and Drummond, D. Allan and Adami, Christoph and Arnold, Frances H. (2005) Thermodynamic prediction of protein neutrality. Proceedings of the National Academy of Sciences of the United States of America, 102 (3). pp. 606-611. ISSN 0027-8424. PMCID PMC545518.

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We present a simple theory that uses thermodynamic parameters to predict the probability that a protein retains the wild-type structure after one or more random amino acid substitutions. Our theory predicts that for large numbers of substitutions the probability that a protein retains its structure will decline exponentially with the number of substitutions, with the severity of this decline determined by properties of the structure. Our theory also predicts that a protein can gain extra robustness to the first few substitutions by increasing its thermodynamic stability. We validate our theory with simulations on lattice protein models and by showing that it quantitatively predicts previously published experimental measurements on subtilisin and our own measurements on variants of TEM1 beta-lactamase. Our work unifies observations about the clustering of functional proteins in sequence space, and provides a basis for interpreting the response of proteins to substitutions in protein engineering applications.

Item Type:Article
Related URLs:
URLURL TypeDescription CentralArticle
Bloom, Jesse D.0000-0003-1267-3408
Wilke, Claus O.0000-0002-7470-9261
Adami, Christoph0000-0002-2915-9504
Arnold, Frances H.0000-0002-4027-364X
Additional Information:© 2005 by the National Academy of Sciences. Edited by Alan R. Fersht, University of Cambridge, Cambridge, United Kingdom, and approved December 3, 2004 (received for review September 10, 2004). This paper was submitted directly (Track II) to the PNAS office. We thank Brian Shoichet for providing us with genes for the TEM1 beta-lactamase variants, Titus Brown for programming assistance, Michelle Meyer and Eric Zollars for helpful advice and discussions, and two anonymous reviewers for helpful comments. J.D.B. is supported by a Howard Hughes Medical Institute predoctoral fellowship. D.A.D. is supported by the National Institutes of Health, National Research Service Award 5 T32 MH19138 from the National Institute of Mental Health. C.A. and C.O.W. were supported in part by the National Science Foundation Grant DEB-9981387.
Funding AgencyGrant Number
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
NIH Predoctoral FellowshipT32 MH19138
Subject Keywords:mutational robustness, protein evolution, protein stability, directed evolution, beta-lactamase, point mutations, sequence space, T4 lysozyme, stability, evolution, model, landscapes, principles, mutants, funnel
Issue or Number:3
PubMed Central ID:PMC545518
Record Number:CaltechAUTHORS:BLOpnas05
Persistent URL:
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:924
Deposited By: Tony Diaz
Deposited On:09 Nov 2005
Last Modified:02 Oct 2019 22:38

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