Dynamic Docking of a Medium-Sized Molecule to Its Receptor by Multicanonical MD Simulations
Dynamic Docking of a Medium-Sized Molecule to Its Receptor by Multicanonical MD Simulations
复制标题
DOI：
10.1021/acs.jpcb.8b12419
复制
发表时间：
2019-03-21
影响因子：
3.3
通讯作者：
Kamiya, Narutoshi
中科院分区：
文献类型：
--
作者：
Bekker, Gert-Jan;Araki, Mitsugu;Kamiya, Narutoshi
一种中等大小和高度灵活的β-分泌酶1（BACE）抑制剂，通过切割其前体蛋白产生淀粉样β-肽，动态对接到BACE的大而宽的催化裂缝结合到淀粉样前体通过采用多规范分子动力学（McMD）模拟。我们应用我们的方法来预测本机绑定配置和样品的中间结构连接这个本机绑定状态的未绑定的。从McMD获得的位于自由能最小值处的代表性结构被取出并进行正则模拟以改进和验证它们，从而再现与最稳定结构中的实验数据一致的天然复合物结构，即，全球最小值的那个。此外，结合自由能通过沿着从McMD系综获得的代表性途径的伞形取样（US）模拟来估计，随后通过加权直方图分析来估计亲和力，其也再现了实验抑制亲和力。有趣的是，两个分子之间的相互作用的损失沿着的途径清楚地显示在自由能景观，重申原子相互作用的受体和药物化合物之间的结合亲和力的根本重要性。美国模拟的采样系综平滑地连接了结合态和未结合态，在保持真实的McMD系综的同时改进了结合途径。
A medium-sized and highly flexible inhibitor to the enzyme beta-secretase 1 (BACE), which produces the amyloid beta-peptide by cleavage of its precursor protein, was dynamically docked into the large and wide catalytic cleft of BACE that binds to the amyloid-precursor by employing multicanonical molecular dynamics (McMD) simulations. We applied our method to predict the native binding configuration and sample the intermediary structures connecting this natively bound state to the unbound one. Representative structures located at free energy minima obtained from McMD were taken and subjected to canonical simulations to refine and validate them, reproducing the native complex structure in agreement with the experimental data in the most stable structure, i.e., the one at the global minimum. In addition, the binding free energy was estimated by umbrella sampling (US) simulations along representative pathways obtained from the McMD ensemble, followed by weighted histogram analysis to estimate the affinity, which also reproduced the experimental inhibitory affinity. Interestingly, the loss of interactions between the two molecules along the pathway was clearly shown in the free energy landscape, reiterating the fundamental importance of atomistic interactions to the binding affinity between receptor and drug compound. The sampled ensemble by the US simulations smoothly connected the bound and unbound states, refining the binding pathway while staying true to the McMD ensemble.