Enzymes and Catalysis – Insights from Valence Bond

Understanding enzyme catalysis and developing ability to control it, is one of the greatest challenges of biochemistry to date. Few successful examples of computational based enzyme design proved the fantastic potential of computational approaches in this field. Yet, relatively modest rate enhancements were reported and further development of complementary methods is still required. The significant progress of the VB methodology within 21^st century enabled, in turn, great progress in the field of enzyme catalysis.^1,2 Our work offers a conceptually simple scheme to identify the specific role that each residue within the enzyme plays in catalysis. The scheme is based on breakdown of the total catalytic effect into contributions of individual protein residues which are further decomposed into chemically interpretable components, using valence bond. The scheme will be demonstrated. It will be shown to shed light on the origin of catalysis in wild-type haloalkane dehalogenase and its mutants. Furthermore, a set of simple rules to select non-optimal sites for catalysis will be described along with possible choice of effective mutations to enhance the enzymatic rate.

References

1. Sharir-Ivry, A., Shnerb, T., Štrajbl, M. & Shurki, A. VB/MM protein landscapes: a study of the S_N2 reaction in haloalkane dehalogenase. Phys. Chem. B 114, 2212-2218 (2010).
2. Sharir-Ivry, A., Rajapandian, V. & Shurki, A. Valence Bond and Enzyme Catalysis: A Time to Breakdown and a Time to Buildup. Eur. J. 21, 7159-7169 (2015).