标题：QM/MM study on the catalytic mechanism of cyclohexane-1,2-dione hydrolase (CDH)
作者：Zhu, Wenyou; Liu, Yongjun
作者机构：[Zhu, Wenyou; Liu, Yongjun] Shandong Univ, Sch Chem & Chem Engn, Key Lab Colloid & Interface Chem, Minist Educ, Jinan 250100, Shandong, Peoples R Chin 更多
通讯作者地址：[Liu, YJ]Shandong Univ, Sch Chem & Chem Engn, Key Lab Colloid & Interface Chem, Minist Educ, Jinan 250100, Shandong, Peoples R China.
来源：THEORETICAL CHEMISTRY ACCOUNTS
关键词：Cyclohexane-1,2-dione (CDO); Cyclohexane-1,2-dione hydrolase (CDH);; Reaction mechanism; QM/MM; Thiamine diphosphate (ThDP)-dependent enzyme
摘要：Cyclohexane-1,2-dione hydrolase (CDH) catalyzes the conversion of cyclohexane-1,2-dione (CDO) to 6-oxohexanoate. It is the first thiamine diphosphate (ThDP)-dependent enzyme that involves a C-C bond ring cleavage of alicyclic compound. In this paper, the detailed catalytic mechanism of CDH has been studied by using quantum mechanics/molecular mechanics approach. Since CDO exists in the form of monohydrated ketone in solution, and one of the two hydroxyl groups may exist in its neutral or deprotonated states, the substrate with different protonation states was firstly docked into the active site by using molecular docking. For the neutral form of CDO, only one binding mode (model A) was observed. In model A, the calculated catalytic reaction involves five elementary steps, and the cleavage of C1(CDO)-C2(ThDP) bond is the rate-limiting step with the energy barrier of 19.9 kcal/mol. For the deprotonated form of CDO, because any one of the two hydroxyl groups may be deprotonated, two binding modes can be found. But only one docking pose (model B) can lead to the conversion of CDO to 6-oxohexanoate, and the corresponding reaction contains three elementary steps, and two of which correspond to comparable energy barriers (15.2 vs 14.5 kcal/mol). Based on our comparison, it is concluded that the C-C bond cleavage is greatly facilitated by the deprotonation of CDO. From the energy point of view, both of the mechanisms derived from models A and B are possible for CDH catalytic reaction.