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The influence of the adjacent hydrogen bond on the hydroxylation processes mediated by cytochrome P450 side-chain cleavage enzyme

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Abstract

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.

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Acknowledgments

This work is supported by National Natural science Foundation of China (Grant Nos. 21003116, 21173211, and 11274096), Innovation Scientists and Technicians Troop Construction Projects of Henan Province (Grant No. 124200510013), and Innovative Research Team in Science and Technology in University of Henan Province (Grant No. 13IRTSTHN016).

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Authors and Affiliations

  1. College of Physics and Electronic Engineer, Henan Normal University, Xinxiang, 453007, China

    Xiaoqian Zhang & Yufang Liu

  2. State Key Laboratory of Molecular Reaction Dynamics, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, China

    Yong Wang

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  1. Xiaoqian Zhang
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  2. Yufang Liu
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  3. Yong Wang
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Correspondence to Yufang Liu or Yong Wang.

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Zhang, X., Liu, Y. & Wang, Y. The influence of the adjacent hydrogen bond on the hydroxylation processes mediated by cytochrome P450 side-chain cleavage enzyme. Theor Chem Acc 133, 1485 (2014). https://doi.org/10.1007/s00214-014-1485-6

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