Relative BAT: An Automated Tool for Relative Binding Free Energy Calculations by the Separated Topologies Approach

Absolute (ABFE) and relative (RBFE) binding free energy calculations with all-atom molecular dynamics (MD) can significantly reduce costs in the early stages of drug discovery. We introduce a new implementation of the Binding Affinity Tool (BAT.py) software, which adds RBFE calculations using separated topologies (SepTop) to the already established ABFE fully automated workflow. SepTop combines the advantages of ABFE and RBFE, being applicable to ligands that have very little or no similarity, while at the same time avoiding common challenges of ABFE calculations, such as occluded binding sites and problematic conformational changes of the receptor upon ligand binding. Three different thermodynamic paths for the relative calculations were implemented into the BAT software using the AMBER and OpenMM simulation engines, and here we test them on the BRD4(2) benchmark system. We discuss their correlation with ABFE, standard RBFE, and experimental results, and also their associated computational cost.全原子分子动力学（Molecular Dynamics, MD）下的绝对结合自由能（Absolute Binding Free Energy, ABFE）与相对结合自由能（Relative Binding Free Energy, RBFE）计算，可显著降低药物发现早期阶段的研发成本。本研究介绍了一款全新的结合亲和力工具（Binding Affinity Tool, BAT.py）软件实现方案，其在已成熟的全自动化ABFE工作流中新增了基于分离拓扑结构（Separated Topologies, SepTop）的RBFE计算功能。分离拓扑结构兼具ABFE与RBFE的优势：既可适用于相似度极低甚至无相似性的配体，同时又能规避ABFE计算中常见的难题，例如结合位点遮蔽以及配体结合时受体出现异常构象变化。本研究依托AMBER与OpenMM两种模拟引擎，在BAT软件中实现了三种适用于相对结合自由能计算的热力学路径，并以BRD4(2)基准测试系统为对象开展了测试。我们还探讨了这些计算结果与ABFE、标准RBFE以及实验结果之间的相关性，同时分析了其对应的计算开销。