Statistical Analysis on the Performance of MolecularMechanics Poisson–Boltzmann Surface Area versus Absolute BindingFree Energy Calculations: Bromodomains as a Case Study

摘要

Binding free energy calculations that make use of alchemical pathways are becoming increasingly feasible thanks to advances in hardware and algorithms. Although relative binding free energy (RBFE) calculations are starting to find widespread use, absolute binding free energy (ABFE) calculations are still being explored mainly in academic settings due to the high computational requirements and still uncertain predictive value. However, in some drug design scenarios, RBFE calculations are not applicable and ABFE calculations could provide an alternative. Computationally cheaper end-point calculations in implicit solvent, such as molecular mechanics Poisson–Boltzmann surface area (MMPBSA) calculations, could too be used if one is primarily interested in a relative ranking of affinities. Here, we compare MMPBSA calculations to previously performed absolute alchemical free energy calculations in their ability to correlate with experimental binding free energies for three sets of bromodomain–inhibitor pairs. Different MMPBSA approaches have been considered, including a standard single-trajectoryprotocol, a protocol that includes a binding entropy estimate, andprotocols that take into account the ligand hydration shell. Despitethe improvements observed with the latter two MMPBSA approaches, ABFEcalculations were found to be overall superior in obtaining correlationwith experimental affinities for the test cases considered. A differencein weighted average Pearson () and Spearman () correlations of 0.25 and 0.31was observedwhen using a standard single-trajectory MMPBSA setup ( = 0.64 and = 0.66for ABFE; = 0.39 and = 0.35for MMPBSA). The best performingMMPBSA protocols returned weighted average Pearson and Spearman correlationsthat were about 0.1 inferior to ABFE calculations: = 0.55 and = 0.56when including an entropy estimate,and = 0.53 and = 0.55when including explicit water molecules.Overall, the study suggests that ABFE calculations are indeed themore accurate approach, yet there is also value in MMPBSA calculationsconsidering the lower compute requirements, and if agreement to experimentalaffinities in absolute terms is not of interest. Moreover, for thespecific protein–ligand systems considered in this study, wefind that including an explicit ligand hydration shell or a bindingentropy estimate in the MMPBSA calculations resulted in significantperformance improvements at a negligible computational cost.