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Proc Natl Acad Sci U S A. 2005 Jan 18;102(3):606-11. Epub 2005 Jan 11.

Thermodynamic prediction of protein neutrality.

Author information

  • 1Division of Chemistry and Chemical Engineering 210-41, California Institute of Technology, Pasadena, CA 91125, USA. bloom@caltech.edu

Abstract

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.

PMID:
15644440
[PubMed - indexed for MEDLINE]
PMCID:
PMC545518
Free PMC Article
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