FEP for Drug Design Including Computation of Absolute Free Energies of Binding
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Both Monte Carlo statistical mechanics and molecular dynamics are being used to compute relative and absolute free energies of binding for protein-ligand complexes. Applications have included computing absolute free energies of binding for L99A lysozyme with benzene and seven analogs, and a drug-like molecule MIF180 with human macrophage migration inhibitory factor (MIF). It is noted that FEP calculations for molecular creations are much more efficient than for annihilations, and strikingly as few as 10 charge and Lennard-Jones windows are needed for creation of MIF180, which has 22 non-hydrogen atoms. Additional computational issues are considered including performance of OPLS-AA/M, CHARMM, and AMBER force fields, atomic charge models, water equilibration, and convergence. Significant advantages in computation speed are reported with MC over MD for similar extents of configurational sampling.