ci7b00347_si_001.pdf (4.16 MB)
Statistical Analysis on the Performance of Molecular Mechanics Poisson–Boltzmann Surface Area versus Absolute Binding Free Energy Calculations: Bromodomains as a Case Study
journal contribution
posted on 2017-08-08, 00:00 authored by Matteo Aldeghi, Michael J. Bodkin, Stefan Knapp, Philip C. BigginBinding
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 (rp̅) and Spearman (rs̅) correlations of 0.25 and 0.31
was observed
when using a standard single-trajectory MMPBSA setup (rp̅ = 0.64 and rs̅ = 0.66
for ABFE; rp̅ = 0.39 and rs̅ = 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: rp̅ = 0.55 and rs̅ = 0.56
when including an entropy estimate,
and rp̅ = 0.53 and rs̅ = 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.