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The influence of the adjacent hydrogen bond on the hydroxylation processes mediated by cytochrome P450 side-chain cleavage enzyme
Zhang, Xiaoqian1; Liu, Yufang1; Wang, Yong2
关键词Cytochrome P450 Enzyme Hydroxylation Density Functional Theoretical Calculation Hydrogen Bond Kinetic Isotope Effect
刊名THEORETICAL CHEMISTRY ACCOUNTS
2014-04-17
DOI10.1007/s00214-014-1485-6
133期:6
收录类别SCI
文章类型Article
WOS标题词Science & Technology ; Physical Sciences
类目[WOS]Chemistry, Physical
研究领域[WOS]Chemistry
关键词[WOS]DENSITY-FUNCTIONAL THERMOCHEMISTRY ; COMPOUND-I ; DISPERSION CORRECTION ; REACTIVITY PATTERNS ; CATALYZED-REACTIONS ; 2-STATE REACTIVITY ; REBOUND MECHANISM ; N-DEMETHYLATION ; ACTIVE-SITE ; CHOLESTEROL
英文摘要The conversion of cholesterol to pregnenolone is a physiologically essential process which initiates with two sequential hydroxylation processes catalyzed by cytochrome P450 side-chain cleavage enzyme (P450SCC). Extensive efforts have been exerted; however, the mechanistic details remain obscure. In this work, we employed the dispersion-corrected density functional theoretical (DFT-D) calculations to investigate the mechanistic details of such hydroxylation processes. Calculated results reveal that the active intermediate Compound I (CpdI) of P450SCC hydroxylates cholesterol efficiently, which coincides with previous spectrometric observations. The hydrogen bond effect of water molecule within the active site lowers the energy barrier significantly. Intriguingly, the adjacent hydrogen bond (H-bond) between the hydroxyl group of the substrate and the oxo group of CpdI in the second hydroxylation affects the H-abstraction significantly. Such H-bond was weakened during the C-H bond activation process, increasing the energy barriers by approximately 2 kcal/mol, which is different to the intermolecular H-bond effect of water903 found by Shaik et al. that decreases the barrier by about 4 kcal/mol. Such adjacent H-bond also affects the transition state by bending the alignment of the C-H-O moiety, and consequently lowering the kinetic isotope effect values. Besides, a series of DFT-D calculations (Grimme's D2, D3-zero, and D3-BJ methods) were performed and accessed to find out an appropriate protocol for H-bond containing hydroxylation process. Our results show that DFT-D single-point energies (SPE) based on geometries optimized with non-dispersion-corrected DFT varies drastically and sometime presents unreasonable results. DFT-D SPE calculations on DFT-D optimized geometries present stable and reasonable results.
语种英语
WOS记录号WOS:000334440700002
引用统计
文献类型期刊论文
条目标识符http://cas-ir.dicp.ac.cn/handle/321008/145644
专题中国科学院大连化学物理研究所
作者单位1.Henan Normal Univ, Coll Phys & Elect Engineer, Xinxiang 453007, Peoples R China
2.Chinese Acad Sci, Dalian Inst Chem Phys, State Key Lab Mol React Dynam, Dalian 116023, Peoples R China
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Zhang, Xiaoqian,Liu, Yufang,Wang, Yong. The influence of the adjacent hydrogen bond on the hydroxylation processes mediated by cytochrome P450 side-chain cleavage enzyme[J]. THEORETICAL CHEMISTRY ACCOUNTS,2014,133(6).
APA Zhang, Xiaoqian,Liu, Yufang,&Wang, Yong.(2014).The influence of the adjacent hydrogen bond on the hydroxylation processes mediated by cytochrome P450 side-chain cleavage enzyme.THEORETICAL CHEMISTRY ACCOUNTS,133(6).
MLA Zhang, Xiaoqian,et al."The influence of the adjacent hydrogen bond on the hydroxylation processes mediated by cytochrome P450 side-chain cleavage enzyme".THEORETICAL CHEMISTRY ACCOUNTS 133.6(2014).
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