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首页> 外文期刊>Journal of Molecular Biology >Some Surprising Implications of NMR-directed Simulations of Substrate Recognition and Binding by Cytochrome P450(cam) (CYP101A1)
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Some Surprising Implications of NMR-directed Simulations of Substrate Recognition and Binding by Cytochrome P450(cam) (CYP101A1)

机译：NMR定向模拟的底物识别和细胞色素P450（CAM）（CYP101A1）的一些令人惊讶的令人惊讶的意义（CYP101A1）

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Cytochrome P450(cam) (CYP101A1) catalyzes the stereospecific 5-exo hydroxylation of d-camphor by molecular oxygen. Previously, residual dipolar couplings measured for backbone amide H-1-N-15 correlations in both substrate-free and bound forms of CYP101A1 were used as restraints in soft annealing molecular dynamic simulations in order to identify average conformations of the enzyme with and without substrate bound. Multiple substrate-dependent conformational changes remote from the enzyme active site were identified, and site-directed mutagenesis and activity assays confirmed the importance of these changes in substrate recognition. The current work makes use of perturbation response scanning (PRS) and umbrella sampling molecular dynamic of the residual dipolar coupling-derived CYP101A1 structures to probe the roles of remote structural features in enforcing the regio- and stereospecific nature of the hydroxylation reaction catalyzed by CYP101A1. An improper dihedral angle 4) was defined and used to maintain substrate orientation in the CYP101A1 active site, and it was observed that different values of LP result in different PRS response maps. Umbrella sampling methods show that the free energy of the system is sensitive to LP, and bound substrate forms an important mechanical link in the transmission of mechanical coupling through the enzyme structure. Finally, a qualitative approach to interpreting PRS maps in terms of the roles of secondary structural features is proposed. (C) 2018 Elsevier Ltd. All rights reserved.
机译：细胞色素P450（CAM）（CYP101A1）通过分子氧催化D-樟脑的立体特异性5- exo羟基化。以前，用于在无基质和结合形式的CYP101A1中的骨干酰胺H-1-N-15相关性测量的残留双极联轴器在软退火分子动态模拟中用作限制，以识别酶的平均构象，而无需底物边界。鉴定了远离酶活性位点的多个基底依赖性构象变化，并且存在定点诱变和活性测定证实了这些变化对基板识别的重要性。目前的工作利用扰动响应扫描（PRS）和伞采样分子动态的残留偶极偶联衍生的CYP101A1结构，以探测远程结构特征在实施CYP101A1催化的羟基化反应的羟基化反应的序列和立体特异性方面的作用。定义了不正确的二面角4）并用于在CYP101A1活性位点中保持基质取向，并且观察到不同的LP值为不同的PRS响应图。伞采样方法表明，系统的自由能对LP敏感，结合的基板通过酶结构传递机械偶联的传输中的重要机械链路。最后，提出了一种在次要结构特征的角色中解释PRS地图的定性方法。 （c）2018年elestvier有限公司保留所有权利。

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