Absolute Free Energy of Binding Calculations for Macrophage Migration Inhibitory Factor in Complex with a Druglike Inhibitor
| Autor: | Jonah Z. Vilseck, Julian Tirado-Rives, Yue Qian, Daniel J. Cole, Israel Cabeza de Vaca, William L. Jorgensen |
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| Rok vydání: | 2019 |
| Předmět: |
Protein Conformation
Entropy Monte Carlo method Thermodynamics Molecular Dynamics Simulation 010402 general chemistry Ligands 01 natural sciences Article Free energy perturbation Molecular dynamics 0103 physical sciences Materials Chemistry Humans Atomic charge Physical and Theoretical Chemistry Enzyme Inhibitors Macrophage Migration-Inhibitory Factors Physics 010304 chemical physics Extramural Sampling (statistics) 0104 chemical sciences Surfaces Coatings and Films Intramolecular Oxidoreductases Macrophage migration inhibitory factor Monte Carlo Method Protein Binding |
| Zdroj: | J Phys Chem B |
| ISSN: | 1520-5207 |
| Popis: | Calculation of the absolute free energy of binding (ΔG(bind)) 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 ΔG(bind) for the complex of a drug-like 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 ΔG(bind) 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 ΔG(bind). These results show that calculation of accurate ΔG(bind) for large ligands is both feasible and numerically equivalent, within error limits, using either methodology. |
| Databáze: | OpenAIRE |
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