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

虽然一般的催化原理，所谓的过渡态稳定化（TST），提出了半个多世纪前，TST的原子细节尚未澄清。除了TST，其他吸引人的假说，如底物扭曲或基态不稳定（GSD），仍然是现代酶学中积极争论的问题。一个这样的实例是乳清酸核苷单磷酸脱羧酶（ODCase），催化乳清酸核苷单磷酸脱羧为尿苷单磷酸的酶。为了回答有争议的问题，我们进行了系统的从头算QM/MM模型结合全电子QM计算的整个蛋白质矩阵。我们的混合建模分析清楚地表明，反应底物具有相当扭曲的几何形状，这种扭曲可以在活化过程中减少高达4千卡/摩尔的能量。TST在这种情况下是关键的催化元素，然而，GSD可以贡献于ODCase反应的催化机理。

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.