Comparison of Receptor-Ligand Restraint Schemes for Alchemical Absolute Binding Free Energy Calculations

Alchemical absolutebinding free energy calculations are of increasinginterest in drug discovery. These calculations require restraintsbetween the receptor and ligand to restrict their relative positionsand, optionally, orientations. Boresch restraints are commonly used,but they must be carefully selected in order to sufficiently restrainthe ligand and to avoid inherent instabilities. Applying multipledistance restraints between anchor points in the receptor and ligandprovides an alternative framework without inherent instabilities whichmay provide convergence benefits by more strongly restricting therelative movements of the receptor and ligand. However, there is nosimple method to calculate the free energy of releasing these restraintsdue to the coupling of the internal and external degrees of freedomof the receptor and ligand. Here, a method to rigorously calculatefree energies of binding with multiple distance restraints by imposingintramolecular restraints on the anchor points is proposed. Absolutebinding free energies for the human macrophage migration inhibitoryfactor/MIF180, system obtained using a variety of Boresch restraintsand rigorous and nonrigorous implementations of multiple distancerestraints are compared. It is shown that several multiple distancerestraint schemes produce estimates in good agreement with Boreschrestraints. In contrast, calculations without orientational restraintsproduce erroneously favorable free energies of binding by up to approximately4 kcal mol(-1). These approaches offer new optionsfor the deployment of alchemical absolute binding free energy calculations.