title: Valence bond and enzyme catalysis: a time to break down and a time to build up.
abstract: Understanding enzyme catalysis and developing ability to control of it are two great challenges in biochemistry. A few successful examples of computational-based enzyme design have proved the fantastic potential of computational approaches in this field, however, relatively modest rate enhancements have been reported and the further development of complementary methods is still required. Herein we propose a conceptually simple scheme to identify the specific role that each residue plays in catalysis. The scheme is based on a breakdown of the total catalytic effect into contributions of individual protein residues, which are further decomposed into chemically interpretable components by using valence bond theory. The scheme is shown to shed light on the origin of catalysis in wild-type haloalkane dehalogenase (wt-DhlA) and its mutants. Furthermore, the understanding gained through our scheme is shown to have great potential in facilitating the selection of non-optimal sites for catalysis and suggesting effective mutations to enhance the enzymatic rate.
authors: Institute for Drug Design, School of Pharmacy, The Lise Meitner-Minerva Center for Computational Quantum Chemistry, The Hebrew University of Jerusalem, Jerusalem 91120 (Israel), Fax: (+972) 2-675-7076.
authors: Avital
authors: A
authors: Sharir-Ivry
authors: Rajapandian
authors: R
authors: Varatharaj
authors: Avital
authors: A
authors: Shurki
mesh_terms: D055162:Biocatalysis; D006867:Hydrolases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D009154:Mutation; D011487:Protein Conformation; D011789:Quantum Theory; D013816:Thermodynamics; D020584:Xanthobacter / Q000737:chemistry / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism
chemical_list: D006867:Hydrolases; C046137:haloalkane dehalogenase
keywords: computational chemistry; enzyme catalysis; enzyme design; quantum mechanics; valence bond theory