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Perturbation Free-Energy Toolkit: An Automated Alchemical Topology Builder
Journal of Chemical Information and Modeling ( IF 5.6 ) Pub Date : 2021-08-20 , DOI: 10.1021/acs.jcim.1c00428
Drazen Petrov 1
Affiliation  

Free-energy calculations play an important role in the application of computational chemistry to a range of fields, including protein biochemistry, rational drug design, or materials science. Importantly, the free-energy difference is directly related to experimentally measurable quantities such as partition and adsorption coefficients, water activity, and binding affinities. Among several techniques aimed at predicting free-energy differences, perturbation approaches, involving the alchemical transformation of one molecule into another through intermediate states, stand out as rigorous methods based on statistical mechanics. However, despite the importance of free-energy calculations, the applicability of the perturbation approaches is still largely impeded by a number of challenges, including the definition of the perturbation path, i.e., alchemical changes leading to the transformation of one molecule to the other. To address this, an automatic perturbation topology builder based on a graph-matching algorithm is developed, which can identify the maximum common substructure (MCS) of two or multiple molecules and provide the perturbation topologies suitable for free-energy calculations using the GROMOS and the GROMACS simulation packages. Various MCS search options are presented leading to alternative definitions of the perturbation pathway. Moreover, perturbation topologies generated using the default multistate MCS search are used to calculate the changes in free energy between lysine and its two post-translational modifications, 3-methyllysine and acetyllysine. The pairwise free-energy calculations performed on this test system led to a cycle closure of 0.5 ± 0.3 and 0.2 ± 0.2 kJ mol–1, with GROMOS and GROMACS simulation packages, respectively. The same relative free energies between the three states are obtained by employing the enveloping distribution sampling (EDS) approach when compared to the pairwise perturbations. Importantly, this toolkit is made available online as an open-source Python package (https://github.com/drazen-petrov/SMArt).

中文翻译:

微扰自由能工具包:自动炼金术拓扑生成器

自由能计算在计算化学在一系列领域的应用中发挥着重要作用,包括蛋白质生物化学、合理的药物设计或材料科学。重要的是,自由能差异与实验可测量的量直接相关,例如分配和吸附系数、水活度和结合亲和力。在旨在预测自由能差异的几种技术中,扰动方法(涉及一种分子通过中间状态转化为另一种分子的炼金术转化)是基于统计力学的严格方法。然而,尽管自由能计算很重要,扰动方法的适用性仍然在很大程度上受到许多挑战的阻碍,包括扰动路径的定义,即,导致一种分子转化为另一种分子的炼金术变化。为了解决这个问题,开发了一种基于图匹配算法的自动扰动拓扑构建器,它可以识别两个或多个分子的最大公共子结构 (MCS),并提供适合使用 GROMOS 和GROMACS 仿真包。提供了各种 MCS 搜索选项,导致扰动路径的替代定义。此外,使用默认多态 MCS 搜索生成的扰动拓扑用于计算赖氨酸与其两种翻译后修饰(3-甲基赖氨酸和乙酰赖氨酸)之间的自由能变化。在该测试系统上执行的成对自由能计算导致循环闭合为 0.5 ± 0.3 和 0.2 ± 0。–1,分别带有 GROMOS 和 GROMACS 仿真包。与成对扰动相比,通过采用包络分布采样 (EDS) 方法获得了三种状态之间相同的相对自由能。重要的是,该工具包作为开源 Python 包在线提供 (https://github.com/drazen-petrov/SMArt)。
更新日期:2021-09-27
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