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In the light of directed evolution: Pathways of adaptive protein evolution

Bloom, Jesse D. and Arnold, Frances H. (2009) In the light of directed evolution: Pathways of adaptive protein evolution. Proceedings of the National Academy of Sciences of the United States of America, 106 (Supple). pp. 9995-10000. ISSN 0027-8424. PMCID PMC2702793. doi:10.1073/pnas.0901522106.

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Directed evolution is a widely-used engineering strategy for improving the stabilities or biochemical functions of proteins by repeated rounds of mutation and selection. These experiments offer empirical lessons about how proteins evolve in the face of clearly-defined laboratory selection pressures. Directed evolution has revealed that single amino acid mutations can enhance properties such as catalytic activity or stability and that adaptation can often occur through pathways consisting of sequential beneficial mutations. When there are no single mutations that improve a particular protein property experiments always find a wealth of mutations that are neutral with respect to the laboratory-defined measure of fitness. These neutral mutations can open new adaptive pathways by at least 2 different mechanisms. Functionally-neutral mutations can enhance a protein's stability, thereby increasing its tolerance for subsequent functionally beneficial but destabilizing mutations. They can also lead to changes in “promiscuous” functions that are not currently under selective pressure, but can subsequently become the starting points for the adaptive evolution of new functions. These lessons about the coupling between adaptive and neutral protein evolution in the laboratory offer insight into the evolution of proteins in nature.

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:Copyright ©2009 by the National Academy of Sciences. Author contributions: J.D.B. and F.H.A. wrote the paper. This paper results from the Arthur M. Sackler Colloquium of the National Academy of Sciences, “In the Light of Evolution III: Two Centuries of Darwin,” held January 16–17, 2009, at the Arnold and Mabel Beckman Center of the National Academies of Sciences and Engineering in Irvine, CA. The complete program and audio files of most presentations are available on the NAS web site at The authors declare no conflict of interest. This article is a PNAS Direct Submission. F.H.A. is supported by the U. S. Department of Energy and the U. S. Army. J.D.B. is supported by a Caltech Beckman Institute Postdoctoral Fellowship and the Irvington Institute Fellowship Program of the Cancer Research Institute.
Funding AgencyGrant Number
Department of Energy (DOE)UNSPECIFIED
Army Research Office (ARO)UNSPECIFIED
Caltech Beckman InstituteUNSPECIFIED
Cancer Research InstituteUNSPECIFIED
Subject Keywords:evolutionary engineering; neutral evolution; promiscuous activity; protein stability; enzyme engineering
Issue or Number:Supple
PubMed Central ID:PMC2702793
Record Number:CaltechAUTHORS:20090812-201735689
Persistent URL:
Official Citation: * Jesse D. Bloom * and Frances H. Arnold Colloquium Papers: In the light of directed evolution: Pathways of adaptive protein evolutionPNAS 2009 106:9995-10000; published online before print June 15, 2009, doi:10.1073/pnas.0901522106
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:15000
Deposited By: George Porter
Deposited On:04 Sep 2009 17:08
Last Modified:08 Nov 2021 23:15

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