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Summary: Enzyme Specificity Under Dynamic Control: A Normal
Mode Analysis of aaa-Lytic Protease
David W. Miller and David A. Agard*
Howard Hughes Medical
Institute and Department of
Biochemistry and Biophysics
University of California at
San Francisco, San Francisco
CA 94143-0448, USA
We have used a-lytic protease as a model system for exploring the
relationship between the internal dynamics of an enzyme and its
substrate speci®city. The wild-type enzyme is highly speci®c for small
substrates in its primary speci®city pocket, while the M190A mutant has
a much broader speci®city, ef®ciently catalyzing cleavage of both large
and small substrates. Normal modes have been calculated for both the
wild-type and the mutant enzyme to determine how internal vibrations
contribute to these contrasting speci®city pro®les. We ®nd that for the
atoms lining the walls of the speci®city pocket, the wild-type normal
modes have a more symmetric character, with the walls vibrating in
phase, and the size of the pocket remaining relatively ®xed. This is in
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