Elucidating the Nature of Enzyme Catalysis Utilizing a New Twist on an Old Methodology:  Quantum Mechanical−Free Energy Calculations on Chemical Reactions in Enzymes and in Aqueous Solution

Abstract

How do enzymes achieve very large rate enhancements compared to corresponding uncatalyzed reactions in solution? We present a computational approach which combines high-level ab initio quantum mechanical calculations with classical free energy calculations to address this question. Our calculations lead to accurate estimates of DeltaG for both trypsin and catechol O-methyltransferase-catalyzed and reference uncatalyzed reactions and give new insights into the nature of enzyme catalysis. The same methodology applied to steps in the catalytic mechanism of citrate synthase further supports the conclusion that one need not invoke special concepts such as "low-barrier hydrogen bonds" or "pK(a) matching" to explain enzyme catalysis.

Mechanisms and Free Energies of Enzymatic Reactions

“…Two methods are generally used, the umbrella sampling technique 30,140 and the free energy perturbation (FEP) theory; 141,142 these methods have been reviewed previously. 45,143 Although FEP theory is exact, 141 in practical FEP applications, 45,142,144 the "perturbation" of the environment (enzyme and solvent) by the structural changes of the substrate from the reactant state to the next sampled point on the reaction path leading to the transition state is assumed to be small. In an extreme version, the free energy of activation can be determined by only considering the interactions between the substrate and enzyme.…”

New developments of polysaccharide synthesis via enzymatic polymerization

“…Second, L. Pauling demonstrated in 1946 the reason why enzymatic reactions proceed under such mild reaction conditions, 19), 20) i.e., the formation of the enzyme-substrate complex stabilizes the transition-state and much lowers the activation energy compared with the no-enzyme case, which is now well accepted (Fig. 4).…”

Uma perspectiva computacional sobre catálise enzimática

“…Por exemplo, a hidrólise de ésteres de fosfato em solução aquosa ocorre diretamente num ataque nucleofílico por uma molécula de água. Porém, a mesma reação catalisada pelas proteínas tirosina-fosfatases (PTPs) ocorre em duas etapas: uma tiólise do éster de fosfato, seguida de uma hidrólise do intermediário tiofosforilado (Figura 1 [18][19][20] .…”