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Summary: In the light of directed evolution: Pathways
of adaptive protein evolution
Jesse D. Blooma
and Frances H. Arnoldb,1
Divisions of aBiology and bChemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125
Directed evolution is a widely-used engineering strategy for im-
proving 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 prop-
erties 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 adap-
tive pathways by at least 2 different mechanisms. Functionally-
neutral mutations can enhance a protein's stability, thereby in-
creasing its tolerance for subsequent functionally beneficial but
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