Abstract
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-trajectory protocol, a protocol that includes a binding entropy estimate, and protocols that take into account the ligand hydration shell. Despite the improvements observed with the latter two MMPBSA approaches, ABFE calculations were found to be overall superior in obtaining correlation with experimental affinities for the test cases considered. A difference in weighted average Pearson () and Spearman () correlations of 0.25 and 0.31 was observed when using a standard single-trajectory MMPBSA setup ( = 0.64 and = 0.66 for ABFE; = 0.39 and = 0.35 for MMPBSA). The best performing MMPBSA protocols returned weighted average Pearson and Spearman correlations that were about 0.1 inferior to ABFE calculations: = 0.55 and = 0.56 when including an entropy estimate, and = 0.53 and = 0.55 when including explicit water molecules. Overall, the study suggests that ABFE calculations are indeed the more accurate approach, yet there is also value in MMPBSA calculations considering the lower compute requirements, and if agreement to experimental affinities in absolute terms is not of interest. Moreover, for the specific protein–ligand systems considered in this study, we find that including an explicit ligand hydration shell or a binding entropy estimate in the MMPBSA calculations resulted in significant performance improvements at a negligible computational cost.
Highlights
On the basis of the data described in this work, which are contingent on the test cases considered, the following observations can be made
(1) Overall, absolute binding free energy (ABFE) calculations appeared to be more robust than molecular mechanics Poisson−Boltzmann surface area (MMPBSA) ones in the ability to correlate to experimental affinities
(4) The inclusion of the binding entropy term, calculated as proposed by Duan et al.,[39] was beneficial for improving the correlation with experiment. This term appeared to be more sensitive to the simulated ensemble than the rest of the MMPBSA terms, potentially affecting the precision of the calculations
Summary
Pathway methods, including alchemical free energy calculations, are Article theoretically rigorous and generally perceived as more accurate than end-point methods; they are computationally much more expensive.[14] rigorous free energy calculations have a smaller number of empirical constants[5] to be adjusted in a system-dependent fashion as compared to MMPBSA, currently they tend to have a less automated and more complex setup, and a number of potential pitfalls.[15,16] Choosing which approach to employ for a specific system and problem at hand can be difficult, as one has to consider whether the additional human and computational cost will be rewarded by a more accurate result
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