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Design by Directed Evolution

Arnold, Frances H. (1998) Design by Directed Evolution. Accounts of Chemical Research, 31 (3). pp. 125-131. ISSN 0001-4842. http://resolver.caltech.edu/CaltechAUTHORS:20171108-085419178

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Abstract

The stunning array of features and functions exhibited by proteins in nature should convince most scientists of the power of evolutionary design processes. Natural selection acting on populations over long periods of time has generated a vast number of proteins ideally suited to their biological functions. When we try to recruit these remarkable molecular machines for new tasksfrom serving as industrial catalysts to being used as additives for laundry detergentswe find that they are often not so well suited. (The chemist is not terribly impressed with a synthesis requiring a reactor the size of a football field simply because the enzyme functions in water and the substrate does not dissolve, nor is she pleased with a catalyst shut down by the products of its own reaction.) Evolution is usually the culprit:  proteins are optimized, and often highly specialized, for specific biological tasks. Most protein reengineering efforts have been by so-called rational design. The filtering effect of scientific publication (successes get published, failures mostly do not) might lead one to believe that we can, with reasonable probability of success, identify and modify the amino acids responsible for key properties such as an enzyme's substrate preference, stability, or activity in a nonnatural environment. In reality, we are far from being able to do this reliably. This is true even for the relatively small number of enzymes for which considerable structural and mechanistic data are available. Admitting ineptitude in rational design, however, frees us to consider other approaches which are hardly irrational. An alternative and highly effective design strategy can be found by looking to the processes by which all these proteins came about in the first place. My research has been devoted to recreating in the laboratory the key processes of evolution and doing it in such a way that we can design scientifically interesting and technologically useful molecules. The challenge is to collapse the time scale for evolution from millions of years to months or even weeks.


Item Type:Article
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https://doi.org/10.1021/ar960017fDOIArticle
http://pubs.acs.org/doi/abs/10.1021/ar960017fPublisherArticle
ORCID:
AuthorORCID
Arnold, Frances H.0000-0002-4027-364X
Additional Information:© 1998 American Chemical Society. Received October 9, 1997. Publication Date (Web): February 28, 1998. I thank the many talented undergraduate, graduate, and postdoctoral students who have contributed great ideas and hard work. This research would not have been possible without the encouragement and support of many colleagues, including Harold Bright, Gene Peterson, Bob Campbell, Pim Stemmer, and Stephen Queener. This research is supported by the Office of Naval Research, the Department of Energy, and the Army Research Office.
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Funding AgencyGrant Number
Office of Naval Research (ONR)UNSPECIFIED
Department of Energy (DOE)UNSPECIFIED
Army Research Office (ARO)UNSPECIFIED
Record Number:CaltechAUTHORS:20171108-085419178
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20171108-085419178
Official Citation:Design by Directed Evolution. Frances H. Arnold. Accounts of Chemical Research 1998 31 (3), 125-131. DOI: 10.1021/ar960017f
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:83057
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:08 Nov 2017 18:13
Last Modified:08 Nov 2017 18:13

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