Molecular mechanism with regard to the binding selectivity of inhibitors toward FABP5 and FABP7 explored by multiple short molecular dynamics simulations and free energy analyses
Molecular mechanism with regard to the binding selectivity of inhibitors toward FABP5 and FABP7 explored by multiple short molecular dynamics simulations and free energy analyses
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DOI：
10.1039/c9cp05704h
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发表时间：
2020-01-28
影响因子：
3.3
通讯作者：
Zhang, Qinggang
中科院分区：
文献类型：
--
作者：
Chen, Jianzhong;Liu, Xinguo;Zhang, Qinggang
近年来，脂肪酸结合蛋白5和7（FABP 5和FABP 7）被认为是临床治疗多种与FABPs相关疾病的潜在靶点。在这项工作中，多个短分子动力学（MSMD）模拟，然后结合自由能计算进行调查的三个抑制剂，即65 X，8 KS，和5 M8对FABP 5和FABP 7的结合选择性。RMSF分析表明，FABP 5的结构柔性比FABP 7强，计算的分子表面积也比FABP 7大。同时，交叉相关分析结果表明，抑制剂结合对FABP 5和FABP 7的内部动力学有不同的影响。通过分子力学/广义玻恩表面积（MM-GBSA）方法预测的结合自由能表明，由抑制剂相对于FABP 5对FABP 7的结合引起的焓变的增加主要驱动抑制剂对FABP 5对FABP 7的结合选择性。通过使用平衡的MSMD轨迹进行基于单独残基的能量贡献和基于残基的自由能分解的计算的层次聚类分析。所获得的结果不仅识别了抑制剂与FABP 5和FABP 7的相互作用热点，而且还显示了几个常见的残基，（T56，T54），（L60，F58），（E75，E73），（A76，A78），（D79，D77），（R81，R79），属于（FABP 5，FABP 7）的（R107，R109），（C120，L118）和（R129，R127）诱导抑制剂对FABP 5和FABP 7的明显结合差异。因此，这些残基在抑制剂对FABP 5和FABP 7的结合选择性中起重要作用。
Recently, fatty acid binding proteins 5 and 7 (FABP5 and FABP7) have been regarded as the prospective targets for clinically treating multiple diseases related to FABPs. In this work, multiple short molecular dynamics (MSMD) simulations followed by binding free energy calculations were performed to investigate the binding selectivity of three inhibitors, namely, 65X, 8KS, and 5M8 toward FABP5 and FABP7. The RMSF analysis suggests that the structural flexibility of FABP5 is stronger than that of FABP7; moreover, the calculated molecular surface area of FABP5 is also larger than that of FABP7. Meanwhile, the results from the cross-correlation analysis show that the inhibitor bindings exert different impacts on the internal dynamics of FABP5 and FABP7. Binding free energies predicted by the molecular mechanics/generalized Born surface area (MM-GBSA) method indicate that the increase in the enthalpy changes caused by the bindings of inhibitors toward FABP7 relative to FABP5 mostly drives the binding selectivity of the inhibitors toward FABP5 versus FABP7. Hierarchical clustering analysis based on the energy contributions of separate residues and calculations of residue-based free energy decompositions were carried out by using the equilibrated MSMD trajectories. The obtained results not only recognize the hot interaction spots of inhibitors with FABP5 and FABP7, but also display that several common residues, namely, (T56, T54), (L60, F58), (E75, E73), (A76, A78), (D79, D77), (R81, R79), (R107, R109), (C120, L118), and (R129, R127) belonging to (FABP5, FABP7) induce obvious binding differences in the inhibitors toward FABP5 and FABP7. Therefore, these residues play significant roles in the binding selectivities of inhibitors toward FABP5 and FABP7.