Effects of Disulfide Bonds on Binding of Inhibitors to β-Amyloid Cleaving Enzyme 1 Decoded by Multiple Replica Accelerated Molecular Dynamics Simulations
Effects of Disulfide Bonds on Binding of Inhibitors to β-Amyloid Cleaving Enzyme 1 Decoded by Multiple Replica Accelerated Molecular Dynamics Simulations
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DOI：
10.1021/acschemneuro.0c00234
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发表时间：
2020-06-17
影响因子：
5
通讯作者：
Sun, Haibo
中科院分区：
文献类型：
--
作者：
Chen, Jianzhong;Yin, Baohua;Sun, Haibo
β-淀粉样蛋白裂解酶1（BACE 1）被认为是治疗阿尔茨海默病（AD）的有效靶点。深入了解BACE 1与BACE 1的结合机制对于设计针对BACE 1的有效药物具有重要意义。在这项工作中，多副本加速分子动力学（MR-aMD）模拟，主成分（PC）分析，和自由能景观集成解码BACE 1中的二硫键（SSB）对三种抑制剂3 KO，3 KT和779 BACE 1的结合的影响。交叉相关分析结果表明，SSBs的断裂对BACE 1的结构柔性和内部动力学特性有显著影响。PC分析和自由能图谱表明，SSBs的断裂不仅明显地诱导了BACE 1的构象重排，而且显著地改变了BACE 1中3种抑制剂的结合位姿，导致3种抑制剂与BACE 1的结合更加无序，这进一步得到了SSBs断裂导致抑制剂与BACE 1结合熵增加的支持.利用基于残基的自由能分解方法来评估不同残基对抑制剂-BACE 1结合的贡献。结果表明，BACE 1中SSBs的断裂虽然没有破坏抑制剂与BACE 1的相互作用网络，但改变了某些残基与抑制剂的相互作用强度。同时，基于残基的自由能分解的信息表明，残基L91、S96、V130、Y132、Q134、W137、F169、1171和1179可以用作针对BACE 1的药物设计的有效靶标。
The beta-amyloid cleaving enzyme 1 (BACE1) has been thought to be an efficient target for treatment of Alzheimer's disease (AD). Deep insight into inhibitor-BACE1 binding mechanism is of significance for design of potent drugs toward BACE1. In this work, multiple replica accelerated molecular dynamics (MR-aMD) simulations, principal component (PC) analysis, and free energy landscapes were integrated to decode the effect of disulfide bonds (SSBs) in BACE1 on bindings of three inhibitors 3KO, 3KT, and 779 to BACE1. The results from cross-correlation analysis suggest that the breaking of SSBs exerts significant influence on structural flexibility and internal dynamics of inhibitor-bound BACE1. PC analysis and free energy landscapes reveal that the breaking of SSBs not only evidently induces the conformational rearrangement of BACE1 but also highly changes binding poses of three inhibitors in BACE1 and leads to more disordered binding of three inhibitors to BACE1, which is further supported by the increase in binding entropy of inhibitors to BACE1 due to the breaking of SSBs. Residue-based free energy decomposition method was utilized to evaluate contributions of separate residues to inhibitor-BACE1 binding. The results suggest that although the breaking of SSBs in BACE1 does not destroy the interaction network of inhibitors with BACE1 it changes interaction strength of some residues with inhibitors. Meanwhile, the information from residue-based free energy decomposition indicates that residues L91, S96, V130, Y132, Q134, W137, F169, 1171, and 1179 can be used as efficient targets of drug design toward BACE1.