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We investigate the role of order/disorder transitions in alchemicalsimulations of protein-ligand absolute binding free energies. We show, in thecontext of a potential of mean force description, that for a benchmarkingsystem (the complex between the L99A mutant of T4 lysozyme and 3-iodotoluene)and for a more challenging system relevant for medicinal applications (thecomplex of the farnesoid X receptor and inhibitor 26 from a recent D3Rchallenge) that order/disorder transitions can significantly hamper Hamiltonianreplica exchange sampling efficiency and slow down the rate of equilibration ofbinding free energy estimates. We further show that our analytical model ofalchemical binding combined with the formalism developed by Straub et al. forthe treatment of order/disorder transitions of molecular systems can besuccessfully employed to analyze the transitions and help design alchemicalschedules and soft-core functions that avoid or reduce the adverse effects ofrare binding/unbinding transitions. The results of this work pave the way forthe application of these techniques to the alchemical estimation with explicitsolvation of hydration free energies and absolute binding free energies ofsystems undergoing order/disorder transitions.

Perturbation Potentials to Overcome Order/Disorder Transitions in Alchemical Binding Free Energy Calculations