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.