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

尽管一般的催化原理，即所谓的过渡态稳定(TST)早在半个多世纪前就被提出了，但TST的原子学细节还没有被阐明。除了TST，其他有吸引力的假说，如底物扭曲或基态失稳(GSD)，仍然是现代酶学中活跃争论的问题。一个这样的例子是一磷酸核苷脱羧酶(ODCase)，该酶催化一磷酸核苷脱羧为尿苷一磷酸。为了回答这些有争议的问题，我们对整个蛋白质基质进行了系统的从头算QM/MM建模，并结合全电子QM计算。我们的混合模拟分析清楚地表明，反应底物具有相当扭曲的几何结构，这种扭曲可以在活化过程中贡献高达4kcal/mol的能量减少。在这种情况下，TST是关键的催化元件，而GSD在ODCase反应中可能起到催化作用。

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.