Extended Metadynamics Protocol for Binding/Unbinding Free Energies of Peptide Ligands to Class A G-Protein-Coupled Receptors.

A metadynamics protocol is presented to characterize the binding and unbinding of peptide ligands to class A G-protein-coupled receptors (GPCRs). The protocol expands on the one previously presented for binding and unbinding small-molecule ligands to class A GPCRs and accounts for the more demanding nature of the peptide binding-unbinding process. It applies to almost all class A GPCRs. Exemplary simulations are described for subtypes Y 1 R, Y 2 R, and Y 4 R of the neuropeptide Y receptor family, vasopressin binding to the vasopressin V 2 receptor (V 2 R), and oxytocin binding to the oxytocin receptor (OTR). Binding free energies and the positions of alternative binding sites are presented and, where possible, compared with the experiment.