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New algorithms and an in silico benchmark for computational enzyme design

¹ Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA
² Molecular Biophysics, Structure & Design Program, University of Washington, Seattle, Washington 98195, USA
³ Department of Chemistry and Pharmacology, Vanderbilt University, Nashville, Tennessee 37232, USA
⁴ Howard Hughes Medical Institute, University of Washington, Seattle, Washington 98195, USA

(RECEIVED May 17, 2006; FINAL REVISION September 29, 2006; ACCEPTED October 2, 2006)

The creation of novel enzymes capable of catalyzing any desired chemical reaction is a grand challenge for computational protein design. Here we describe two new algorithms for enzyme design that employ hashing techniques to allow searching through large numbers of protein scaffolds for optimal catalytic site placement. We also describe an in silico benchmark, based on the recapitulation of the active sites of native enzymes, that allows rapid evaluation and testing of enzyme design methodologies. In the benchmark test, which consists of designing sites for each of 10 different chemical reactions in backbone scaffolds derived from 10 enzymes catalyzing the reactions, the new methods succeed in identifying the native site in the native scaffold and ranking it within the top five designs for six of the 10 reactions. The new methods can be directly applied to the design of new enzymes, and the benchmark provides a powerful in silico test for guiding improvements in computational enzyme design.

Keywords: enzyme design; protein design; active site recapitulation; protein–ligand interactions; geometric hashing

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