Absolute Free Energy of Binding Calculations for Macrophage Migration Inhibitory Factor in Complex with a Druglike Inhibitor

Calculation of the
absolute free energy of binding (ΔGbind) for a complex in solution is challenging
owing to the need for adequate configurational sampling and an accurate
energetic description, typically with a force field (FF). In this
study, Monte Carlo (MC) simulations with improved side-chain and backbone
sampling are used to assess ΔGbind for the complex of a druglike inhibitor (MIF180) with the protein
macrophage migration inhibitory factor (MIF) using free energy perturbation
(FEP) calculations. For comparison, molecular dynamics (MD) simulations
were employed as an alternative sampling method for the same system.
With the OPLS-AA/M FF and CM5 atomic charges for the inhibitor, the
ΔGbind results from the MC/FEP and
MD/FEP simulations, −8.80 ± 0.74 and −8.46 ±
0.85 kcal/mol, agree well with each other and with the experimental
value of −8.98 ± 0.28 kcal/mol. The convergence of the
results and analysis of the trajectories indicate that sufficient
sampling was achieved for both approaches. Repeating the MD/FEP calculations
using current versions of the CHARMM and AMBER FFs led to a 6 kcal/mol
range of computed ΔGbind. These
results show that calculation of accurate ΔGbind for large ligands is both feasible and numerically
equivalent, within error limits, using either methodology.