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Protein stability promotes evolvability

Bloom, Jesse D. and Labthavikul, Sy T. and Otey, Christopher R. and Arnold, Frances H. (2006) Protein stability promotes evolvability. Proceedings of the National Academy of Sciences of the United States of America, 103 (15). pp. 5869-5874. ISSN 0027-8424. PMCID PMC1458665.

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The biophysical properties that enable proteins to so readily evolve to perform diverse biochemical tasks are largely unknown. Here, we show that a protein’s capacity to evolve is enhanced by the mutational robustness conferred by extra stability. We use simulations with model lattice proteins to demonstrate how extra stability increases evolvability by allowing a protein to accept a wider range of beneficial mutations while still folding to its native structure. We confirm this view experimentally by mutating marginally stable and thermostable variants of cytochrome P450 BM3. Mutants of the stabilized parent were more likely to exhibit new or improved functions. Only the stabilized P450 parent could tolerate the highly destabilizing mutations needed to confer novel activities such as hydroxylating the antiinflammatory drug naproxen. Our work establishes a crucial link between protein stability and evolution. We show that we can exploit this link to discover protein functions, and we suggest how natural evolution might do the same.

Item Type:Article
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URLURL TypeDescription CentralArticle
Bloom, Jesse D.0000-0003-1267-3408
Arnold, Frances H.0000-0002-4027-364X
Additional Information:© 2006 by The National Academy of Sciences of the USA Edited by Michael Levitt, Stanford University School of Medicine, Stanford, CA, and approved February 14, 2006 (received for review November 21, 2005). This paper was submitted directly (Track II) to the PNAS office. Published online before print March 31, 2006, 10.1073/pnas.0510098103 We thank M. Landwehr for bountiful advice and the synthesis of 12-pNCA and C. O. Wilke for helpful advice. J.D.B. is supported by a Howard Hughes Medical Institute predoctoral fellowship. This work was supported by National Institutes of Health Grant R01 GM068664-01. This work was inspired, in part, by a Santa Fe Institute workshop on Evolutionary Innovations supported by a grant from the Packard Foundation. Author contributions: J.D.B. and F.H.A. designed research; J.D.B. and S.T.L. performed research; C.R.O. contributed new reagents/analytic tools; J.D.B., C.R.O., and F.H.A. analyzed data; and J.D.B. wrote the paper. Conflict of interest statement: No conflicts declared.
Subject Keywords:CYP102A1; cytochrome P450; directed evolution; lattice protein; mutational robustness
Issue or Number:15
PubMed Central ID:PMC1458665
Record Number:CaltechAUTHORS:BLOpnas06
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:5069
Deposited By: Archive Administrator
Deposited On:26 Sep 2006
Last Modified:02 Oct 2019 23:19

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