Absolute Free Energy of Binding Calculations for Macrophage Migration Inhibitory Factor in Complex with a Druglike Inhibitor
2019
Qian, Yue | Cabeza de Vaca, Israel | Vilseck, Jonah Z. | Cole, Daniel J. | Tirado-Rives, Julian | Jorgensen, William L.
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.
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