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题名: The influence of the adjacent hydrogen bond on the hydroxylation processes mediated by cytochrome P450 side-chain cleavage enzyme
作者: 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
发表日期: 2014-04-17
DOI: 10.1007/s00214-014-1485-6
卷: 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
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.
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
语种: 英语
WOS记录号: WOS:000334440700002
Citation statistics: 
内容类型: 期刊论文
URI标识: http://cas-ir.dicp.ac.cn/handle/321008/145644
Appears in Collections:中国科学院大连化学物理研究所_期刊论文

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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

Recommended Citation:
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).
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