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首页> 外文期刊>Journal of chemical information and modeling >Binding Analysis of Some Classical Acetylcholinesterase Inhibitors: Insights for a Rational Design Using Free Energy Perturbation Method Calculations with QM/MM MD Simulations
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Binding Analysis of Some Classical Acetylcholinesterase Inhibitors: Insights for a Rational Design Using Free Energy Perturbation Method Calculations with QM/MM MD Simulations

机译：一些经典乙酰胆碱酯酶抑制剂的结合分析：利用QM / MM MD模拟使用自由能扰动方法计算的合理设计见解

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摘要

In the present study, the binding free energy of some classical inhibitors (DMT, DNP, GNT, HUP, THA) with acetylchdlinesterase (AChE) is calculated by means of the free energy perturbation (FEP) method based on hybrid quantum mechanics and molecular mechanics (QM/MM) potentials. The results highlight the key role of the van der Waals interaction for the inhibition process, since the contribution of this term to the binding free energy is almost as decisive as the electrostatic one. The analysis of the geometrical parameters and the interaction energy per residue along the QM/MM molecular dynamics (MD) simulations highlights the most relevant interactions in the different AChE ligand systems, showing that the charged residues with a more prominent contribution to the interaction energy are Asp72 and Glu199, although the relative importance depends on the molecular size of the ligand. A correlation between the binding free energy and the number of cation-2c interactions present in the systems has been established, DMT being the most potent inhibitor, capable of forming four cation-7c interactions. A layer of water molecules surrounding the inhibitors has been observed, which act as bridges along a network formed by the ligands and the residues of the gorge and also between different residues. Although several hydrogen bonds between ligands and AChE do appear, no significant values of BIEs have been recorded. This behavior can be accounted for by the special features of AChE, such as the presence of several subsites of different natures in the gorge or the existence of several water molecules that act as bridges in the electrostatic interactions.
机译：在本研究中，通过基于杂交量子力学和分子力学的自由能扰动（FEP）法计算一些经典抑制剂（DMT，DNP，GNT，HUP，THA）的结合自由能（DMT，DNP，GNT，HUP，THA）计算（QM / mm）电位。结果突出了van der Wa的相互作用对抑制过程的关键作用，因为该术语对绑定能量的贡献几乎与静电液一样决定性。沿QM / MM分子动力学（MD）模拟的几何参数和每个残留物的相互作用能量的分析突出了不同ACHE配体系统中最相关的相互作用，表明带有更突出对互动能量的带电残余物ASP72和GLU199，但相对重要性取决于配体的分子大小。已经建立了结合自由能与系统中存在的阳离子-2C相互作用之间的相关性，DMT是最有效的抑制剂，能够形成四种阳离子-7C相互作用。已经观察到围绕抑制剂周围的水分子，其沿着由配体形成的网络和峡谷的残留物和不同残留物之间的桥接作用。尽管配体和疼痛之间的几个氢键显示出来，但没有记录未显着的珠子值。这种行为可以通过ACHE的特殊特征来占，例如在峡谷中存在几个不同性质的子物或几个用于静电相互作用桥的水分子的存在。

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