Elucidating the nature of enzyme catalysis utilizing a new twist on an oldmethodology: Quantum mechanical - Free energy calculations on chemical reactions in enzymes and in aqueous solution

How do enzymes achieve very large rate enhancements compared to correspondi ng uncatalyzed reactions in solution? We present a computational approach w hich combines high-level ab initio quantum mechanical calculations with cla ssical free energy calculations to address this question. Our calculations lead to accurate estimates of DeltaG double dagger for both trypsin and cat echol O-methyltransferase-catalyzed and reference uncatalyzed reactions and give new insights into the nature of enzyme catalysis. The same methodolog y applied to steps in the catalytic mechanism of citrate synthase further s upports the conclusion that one need not invoke special concepts such as "l ow-barrier hydrogen bonds" or "pK(a) matching" to explain enzyme catalysis.