Large scale relative protein ligand binding affinities using non-equilibrium alchemy.
Large scale relative protein ligand binding affinities using non-equilibrium alchemy.
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DOI：
10.1039/c9sc03754c
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发表时间：
2019-12-02
期刊：
影响因子：
8.4
通讯作者：
de Groot BL
中科院分区：
文献类型：
--
作者：
Gapsys V;Pérez-Benito L;Aldeghi M;Seeliger D;van Vlijmen H;Tresadern G;de Groot BL
基于分子动力学（MD）模拟和非物理（炼金术）热力学循环的配体结合亲和力计算已经显示出基于结构的药物设计的巨大前景。然而，它们的广泛吸收和影响受到了众所周知的复杂计算设置的阻碍。只有少数工具以外的自由能微扰方法薛定谔公司。（称为FEP+）目前支持端到端应用。在这里，我们首次提出了一种基于开源软件pmx的方法，该方法允许使用GROMACS MD引擎轻松设置和运行不同小分子组的炼金术计算。该方法依赖于理论上严格的非平衡热力学积分（TI）的基础上，其灵活性允许计算与多个力场。在本研究中，将Amber和Charmm力场的结果结合起来，以产生与商业FEP+方法相当的一致结果。来自13个不同蛋白质-配体数据集的482个扰动的大数据集导致平均无符号误差（AUE）为3.64 ± 0.14 kJ mol−1，相当于薛定谔的FEP+ AUE为3.66 ± 0.14 kJ mol−1。首次提出了一种基于开源软件的整体高精度和高准确度相对蛋白质-配体炼金术自由能计算的方法。基于分子动力学（MD）模拟和非物理（炼金术）热力学循环的相对配体结合亲和力计算显示出基于结构的药物设计的巨大前景。
Ligand binding affinity calculations based on molecular dynamics (MD) simulations and non-physical (alchemical) thermodynamic cycles have shown great promise for structure-based drug design. However, their broad uptake and impact is held back by the notoriously complex setup of the calculations. Only a few tools other than the free energy perturbation approach by Schrödinger Inc. (referred to as FEP+) currently enable end-to-end application. Here, we present for the first time an approach based on the open-source software pmx that allows to easily set up and run alchemical calculations for diverse sets of small molecules using the GROMACS MD engine. The method relies on theoretically rigorous non-equilibrium thermodynamic integration (TI) foundations, and its flexibility allows calculations with multiple force fields. In this study, results from the Amber and Charmm force fields were combined to yield a consensus outcome performing on par with the commercial FEP+ approach. A large dataset of 482 perturbations from 13 different protein–ligand datasets led to an average unsigned error (AUE) of 3.64 ± 0.14 kJ mol−1, equivalent to Schrödinger's FEP+ AUE of 3.66 ± 0.14 kJ mol−1. For the first time, a setup is presented for overall high precision and high accuracy relative protein–ligand alchemical free energy calculations based on open-source software. Relative ligand binding affinity calculations based on molecular dynamics (MD) simulations and non-physical (alchemical) thermodynamic cycles have shown great promise for structure-based drug design.
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影响因子：
4.1
作者：
BENNETT, CH
通讯作者：
BENNETT, CH
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通讯作者：
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影响因子：
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作者：
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通讯作者：
de Groot, Bert L.