Catalysis: transition-state molecular recognition?

The key to understanding the fundamental processes of catalysis is the transition state (TS): indeed, catalysis is a transition-state molecular recognition event. Practical objectives, such as the design of TS analogues as potential drugs, or the design of synthetic catalysts (including catalytic antibodies), require prior knowledge of the TS structure to be mimicked. Examples, both old and new, of computational modelling studies are discussed, which illustrate this fundamental concept. It is shown that reactant binding is intrinsically inhibitory, and that attempts to design catalysts that focus simply upon attractive interactions in a binding site may fail. Free-energy changes along the reaction coordinate for S(N)2 methyl transfer catalysed by the enzyme catechol-O-methyl transferase are described and compared with those for a model reaction in water, as computed by hybrid quantum-mechanical/molecular-mechanical molecular dynamics simulations. The case is discussed of molecular recognition in a xylanase enzyme that stabilises its sugar substrate in a (normally unfavourable) boat conformation and in which a single-atom mutation affects the free-energy of activation dramatically.