Molecular basis of P450 OleTJE: an investigation of substrate binding mechanism and major pathways
Molecular basis of P450 OleTJE: an investigation of substrate binding mechanism and major pathways
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P450 OleT(JE)的分子基础：底物结合机制和主要途径的研究
DOI：
10.1007/s10822-017-0013-x
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发表时间：
2017-05-01
影响因子：
3.5
通讯作者：
Yang, Jian Ming
中科院分区：
文献类型：
--
作者：
Du, Juan;Liu, Lin;Yang, Jian Ming
细胞色素P450olet(JE)能催化长链脂肪酸脱羧生成烯烃，不仅是生物燃料分子，还可广泛用于制造润滑剂、聚合物和洗涤剂。本研究通过常规分子动力学模拟和结合自由能计算，研究了P450分子筛(JE)与花生四烯酸、肉豆蔻酸和辛酸的结合机理。此外，随机加速分子动力学(RAMD)模拟揭示了不同脂肪酸最可能的进出通道。预测的结合自由能大小顺序为花生酸、肉豆蔻酸和辛酸。确定了与三种底物相互作用的关键残基和与其中一种底物特异结合的残基。RAMD结果表明，花生四烯酸、肉豆蔻酸和辛酸最可能的通道分别是2e/2b、2a和2f/2a。根据底物上Hβ原子相对于化合物I态的距离，认为在肉豆蔻酸键合体系中反应比在花生四烯酸和辛酸键合体系中更容易进行。本研究为理解P450 olet(JE)的底物偏好机制提供了新的见解，并为设计合理的短链脂肪酸脱羧酶提供了有价值的信息。
Cytochrome P450 OleT(JE) has attracted much attention for its ability to catalyze the decarboxylation of long chain fatty acids to generate alkenes, which are not only biofuel molecule, but also can be used broadly for making lubricants, polymers and detergents. In this study, the molecular basis of the binding mechanism of P450 OleT(JE) for arachidic acid, myristic acid, and caprylic acid was investigated by utilizing conventional molecular dynamics simulation and binding free energy calculations. Moreover, random acceleration molecular dynamics (RAMD) simulations were performed to uncover the most probable access/egress channels for different fatty acids. The predicted binding free energy shows an order of arachidic acid < myristic acid < caprylic acid. Key residues interacting with three substrates and residues specifically binding to one of them were identified. The RAMD results suggest the most likely channel for arachidic acid, myristic acid, and caprylic acid are 2e/2b, 2a and 2f/2a, respectively. It is suggested that the reaction is easier to carry out in myristic acid bound system than those in arachidic acid and caprylic acid bound system based on the distance of H beta atom of substrate relative to P450 OleT(JE) Compound I states. This study provided novel insight to understand the substrate preference mechanism of P450 OleT(JE) and valuable information for rational enzyme design for short chain fatty acid decarboxylation.