Accurate determination of protein:ligand standard binding free energies from molecular dynamics simulations
Accurate determination of protein:ligand standard binding free energies from molecular dynamics simulations
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DOI：
10.1038/s41596-021-00676-1
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发表时间：
2022-03-11
期刊：
影响因子：
14.8
通讯作者：
Chipot, Christophe
中科院分区：
文献类型：
--
作者：
Fu, Haohao;Chen, Haochuan;Chipot, Christophe
设计一种可靠的计算方法来计算蛋白质：配体标准结合自由能是极其具有挑战性的。配基和蛋白质的结合所伴随的构型焓和构型熵的巨大变化，在幼稚的蛮力模拟中是出了名的难捕捉的。针对这一问题，本方案依赖于确定蛋白质的严格统计机械框架：配体结合亲和力以及全面的结合自由能估计器2(BFEE2)应用软件。根据从实验或对接中获得的结合状态的知识，应用具有可靠力场的BFEE2协议在几天内为广泛的蛋白质：配体复合体提供化学精度内的标准结合自由能。本协议描述了如何使用结合自由能估计器2(BFEE2)软件来计算各种蛋白质：具有不同性质的配体复合体的标准结合自由能。
Designing a reliable computational methodology to calculate protein:ligand standard binding free energies is extremely challenging. The large change in configurational enthalpy and entropy that accompanies the association of ligand and protein is notoriously difficult to capture in naive brute-force simulations. Addressing this issue, the present protocol rests upon a rigorous statistical mechanical framework for the determination of protein:ligand binding affinities together with the comprehensive Binding Free-Energy Estimator 2 (BFEE2) application software. With the knowledge of the bound state, available from experiments or docking, application of the BFEE2 protocol with a reliable force field supplies in a matter of days standard binding free energies within chemical accuracy, for a broad range of protein:ligand complexes. Limiting undesirable human intervention, BFEE2 assists the end user in preparing all the necessary input files and performing the post-treatment of the simulations towards the final estimate of the binding affinity.This protocol describes how to use the Binding Free-Energy Estimator 2 (BFEE2) software to calculate the standard binding free energy of a variety of protein:ligand complexes with different properties.