生物学杂志

生物学杂志 ›› 2022, Vol. 39 ›› Issue (3): 41-.doi: 10.3969/j.issn.2095-1736.2022.03.041

• 研究报告 • 上一篇    下一篇

基于理论计算探究CYP4F12催化花生四烯酸机制

  

  1. 天津医科大学 生物医学工程与技术学院， 天津 300070
  • 出版日期:2022-06-18 发布日期:2022-06-17
  • 通讯作者: 张美玲，博士，教授，研究方向为生物物理、计算机辅助药物设计，E-mail：mlzhang@tmu.edu.cn
  • 作者简介:吕旭东，硕士在读，研究方向为生物物理、计算机辅助药物设计，E-mail：sxsxyxlxd@163.com
  • 基金资助:
    国家自然科学基金项目(No.10904111, No.11604238)；天津市自然科学基金项目(No.11JCYBJC14500)；天津市教委科研计划项目(No.2019KJ175)

The mechanism of arachidonic acid catalyzed by CYP4F12 based on theoretical calculations

  1. School of Biomedical Engineering and Technology, Tianjin Medical University, Tianjin 300070, China
  • Online:2022-06-18 Published:2022-06-17

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摘要： 为分析细胞色素P450(CYP)4F12催化花生四烯酸（AA）的反应过程，使用密度泛函理论（DFT）、同源建模、分子对接和分子动力学（MD）模拟进行计算研究。基于花生四烯酸与血红素基团最终氧化物（Cpd I）模型的密度泛函理论计算表明，ω-2位点羟基化的能垒比其他潜在代谢位点的能垒低约5～26 kJ/mol。ERRAT、PROCHECK等证实建模蛋白具有良好的结构特征。分子对接与分子动力学模拟的结果表明，ω-2位点在催化过程中更易接近活性氧原子，且活性位点附近氨基酸残基Asn122和Ser399在稳定底物中起主要作用。结合自由能分析也表明，氨基酸残基Asn122和Ser399对催化发生具有重大贡献。研究揭示CYP4F12催化花生四烯酸的结合模式，为研究CYP4酶提供了研究思路和理论指导。

关键词: 细胞色素P450酶4F12, 密度泛函理论, 分子动力学模拟

Abstract: To study the reaction of cytochrome enzyme P450 (CYP) 4F12 catalyzed by arachidonic acid (AA), we used density functional theory (DFT), homology modeling, molecular docking, and molecular dynamics (MD) simulations to perform a computational study on the interaction of CYP4F12 and arachidonic acid (AA). The DFT calculation based on the model of arachidonic acid and heme group showed that the energy barrier of hydroxylation at the ω-2 site was about 5-26 kJ/mol lower than that of other potential metabolic sites. The results of ERRAT and PROCHECK confirmed that the modeled protein has a good quality.The results of molecular docking and molecular dynamics simulations showed that the ω-2 site was more accessible to active oxygen atoms in the catalytic process, and the amino acid residues ASN122 and SER399 near the active site played a major role in stabilizing the substrate. Binding free energy analysis also showed that the amino acid residues ASN122 and SER399 had a significant contribution to catalysis. Our research revealed the binding mode of arachidonic acid catalyzed by CYP4F12, which provided research ideas and theoretical guidance for the study of CYP 4 enzymes.

Key words: cytochrome P450 4F12 (CYP4F12), density functional theory, molecular dynamics simulation

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