Mechanistic principle of protein functions: computational approach based on the free energy analyses

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Although the general catalytic principle, so-called the transition state stabilization (TST), was proposed over half a century ago, atomistic details of TST have not yet been clarified. Besides TST, other appealing hypotheses, such as the substrate distortion or ground state destabilization (GSD), are still actively debated issues in modern enzymology. One such example is orotidine monophosphate decarboxylase (ODCase), the enzyme that catalyzes the decarboxylation of orotidine monophosphate to uridine monophosphate. To answer the controversial issues, we performed systematic ab initio QM/MM modeling combined with all-electron QM calculation for the entire protein matrix. Our hybrid modeling analyses clearly showed that the reactive substrate has rather distorted geometry, and this distortion can contribute up to 4 kcal/mol energy reduction in the activation process. TST in this case is the key catalytic element, however, GSD can contribute to the catalytic mechanism in ODCase reaction.