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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
KeywordCytochrome P450 Enzyme Hydroxylation Density Functional Theoretical Calculation Hydrogen Bond Kinetic Isotope Effect
Source PublicationTHEORETICAL CHEMISTRY ACCOUNTS
2014-04-17
DOI10.1007/s00214-014-1485-6
Volume133Issue:6
Indexed BySCI
SubtypeArticle
WOS HeadingsScience & Technology ; Physical Sciences
WOS SubjectChemistry, Physical
WOS Research AreaChemistry
WOS KeywordDENSITY-FUNCTIONAL THERMOCHEMISTRY ; COMPOUND-I ; DISPERSION CORRECTION ; REACTIVITY PATTERNS ; CATALYZED-REACTIONS ; 2-STATE REACTIVITY ; REBOUND MECHANISM ; N-DEMETHYLATION ; ACTIVE-SITE ; CHOLESTEROL
AbstractThe 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.
Language英语
WOS IDWOS:000334440700002
Citation statistics
Document Type期刊论文
Identifierhttp://cas-ir.dicp.ac.cn/handle/321008/145644
Collection中国科学院大连化学物理研究所
Affiliation1.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
GB/T 7714
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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