On the origin of the chemical barrier and tunneling in enzymes

Abstract

This paper presents both a review of some recent results from our group and experimental groups, and some new theoretical results all of which are helping to form a more physically rigorous picture of the process of enzymatic catalysis. A common classical picture of enzymatic catalysis is the transition state tight binding model. Schwartz and Schramm (Nat. Chem. Biol. 2009, 5, 551-558.) have recently argued from both theoretical and experimental results that this picture is incorrect. We now investigate what the nature of barriers might be in enzymatic reactions, and what this viewpoint might imply for tunneling in a hydrogen transfer enzyme. For lactate dehydrogenase we conclude that the enzymes role in catalysis is at least partially to hunt through configuration space for those configurations that minimize chemical free energy barriers. Those configurations do not seem to be stable basins on the free energy surface, and in fact the overall free energy barrier to reaction may well largely be due to this stochastic hunt-both probabilistically and energetically. We suggest further computations to test this hypothesis