g_mmpbsa-A GROMACS Tool for High-Throughput MM-PBSA Calculations
g_mmpbsa-A GROMACS Tool for High-Throughput MM-PBSA Calculations
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DOI：
10.1021/ci500020m
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发表时间：
2014-07-01
影响因子：
5.6
通讯作者：
Lynn, Andrew
中科院分区：
文献类型：
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作者：
Kumari, Rashmi;Kumar, Rajendra;Lynn, Andrew
分子力学泊松-玻尔兹曼表面积（MM-PBSA）是一种估算相互作用自由能的方法，在生物分子相互作用研究中得到了越来越多的应用。最近，该方法也被应用于计算药物设计中的评分函数。这里介绍一个新工具g_mmpbsa，它使用内部编写的子例程或来自GROMACS和APBS包的子例程实现MM-PBSA方法。g_mmpbsa是作为开源药物发现（OSDD）联盟的一部分开发的。其目的是将高通量分子动力学（MD）模拟与结合能计算相结合。该工具提供了选择替代原子半径和不同的非极性溶剂化模型的选项，包括基于溶剂可达表面积（SASA），溶剂可达体积（SAV）的模型，以及包含排斥（SASA-SAV）和吸引成分的模型（使用Weeks-Chandler-Andersen类积分方法描述）。通过比较37种结构不同的HIV-1蛋白酶抑制剂复合物的计算相互作用能与其实验结合自由能，我们展示了该工具的有效性。研究了原子半径、介电常数、网格分辨率、溶质溶剂介电边界定义和非极性模型等输入参数组合变化的影响。G_mmpbsa也可用来估计每个残基对结合能的能量贡献。它已被用于鉴定HIV-1蛋白酶中对结合一系列抑制剂最关键的残基。
Molecular mechanics Poisson-Boltzmann surface area (MM-PBSA), a method to estimate interaction free energies, has been increasingly used in the study of biomolecular interactions. Recently, this method has also been applied as a scoring function in computational drug design. Here a new tool g_mmpbsa, which implements the MM-PBSA approach using subroutines written in-house or sourced from the GROMACS and APBS packages is described. g_mmpbsa was developed as part of the Open Source Drug Discovery (OSDD) consortium. Its aim is to integrate high-throughput molecular dynamics (MD) simulations with binding energy calculations. The tool provides options to select alternative atomic radii and different nonpolar solvation models including models based on the solvent accessible surface area (SASA), solvent accessible volume (SAV), and a model which contains both repulsive (SASA-SAV) and attractive components (described using a Weeks-Chandler-Andersen like integral method). We showcase the effectiveness of the tool by comparing the calculated interaction energy of 37 structurally diverse HIV-1 protease inhibitor complexes with their experimental binding free energies. The effect of varying several combinations of input parameters such as atomic radii, dielectric constant, grid resolution, solute solvent dielectric boundary definition, and nonpolar models was investigated. g_mmpbsa can also be used to estimate the energy contribution per residue to the binding energy. It has been used to identify those residues in HIV-1 protease that are most critical for binding a range of inhibitors.