How mutations affecting the ligand-receptor interactions: a combined MD and QM/MM calculation on CYP2E1 and its two mutants
How mutations affecting the ligand-receptor interactions: a combined MD and QM/MM calculation on CYP2E1 and its two mutants
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DOI：
10.1007/s40242-015-5071-9
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发表时间：
2015-05
影响因子：
3.1
通讯作者：
Wang Yan;Qingchuan Zheng;Jilong Zhang;Xie Mo;Zhan Jiuyu;Hong-Xing Zhang
中科院分区：
文献类型：
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作者：
Wang Yan;Qingchuan Zheng;Jilong Zhang;Xie Mo;Zhan Jiuyu;Hong-Xing Zhang
细胞色素P450(CYP)2E1是一种双功能单加氧酶，在目前市场上6%的药物的代谢中发挥着至关重要的作用。这种酶因其与饮酒、糖尿病、肥胖和禁食的关系而受到极大关注。尽管有丰富的实验诱变数据，但酶活性缺陷的分子起源和结构基序尚未在原子水平上合理化。在这方面，我们研究了CYP2E1、N219D和S366C单点突变时突变对结构和能量特征的影响。对CYP2E1及其两个突变体进行分子动力学（MD）模拟结合量子力学/分子力学（QM/MM）和非共价相互作用（NCI）分析。结果强调了 Phe207 的关键作用，它负责结构灵活性和能量变化，缩短了酶活性降低的理论与实验观察结果之间的差距。突变体酶活性缺陷的潜在分子机制可能归因于两个突变体中 Phe207 空间位置的变化。这项工作基于 MD 和 QM/MM 的组合计算，对突变如何影响配体-受体相互作用提供了具体的解释。此外，本研究中获得的对 CYP2E1 活性的突变效应有利于 CYP 的实验和计算工作，并可能使研究人员能够实现酶活性的理想变化。
Cytochrome P450(CYP) 2E1 is a dual function monoxygenase with a crucial role in the metabolism of 6% of drugs on the market at present. The enzyme is of tremendous interest for its association with alcohol consumption, diabetes, obesity and fasting. Despite the abundant experimental mutagenesis data, the molecular origin and the structural motifs for the enzymatic activity deficiencies have not been rationalized at the atomic level. In this regard, we have investigated the effects of mutation on the structural and energetic characteristics upon single point mutations in CYP2E1, N219D and S366C. The molecular dynamics(MD) simulation combined with quantum mechanics/molecular mechanics(QM/MM) and noncovalent interaction(NCI) analysis was carried out on CYP2E1 and its two mutants. The results highlight the critical role of Phe207, which is responsible for both structural flexibility and energetic variation, shortening the gap between the theory and the experimentally observed results of enzymatic activity decrease. The underlying molecular mechanism of the enzymatic activity deficiencies for mutants may be attributed to the changes of spatial position of Phe207 in the two mutants. This work provides particular explanations to how mutations affect ligand-receptor interactions based on combined MD and QM/MM calculations. Furthermore, the mutational effects on the activity of CYP2E1 obtained in the present study are beneficial to both the experimental and the computational works of CYPs and may allow researchers to achieve desirable changes in enzymatic activity.