Unraveling Binding Interactions between Human RANKL and Its Decoy Receptor Osteoprotegerin

Recent studies have revealed the importance and the active contribution of the RANKL/OPG/RANK pathway in many bone diseases including different forms of common osteoporosis. In this study, we present an extensive atomistic molecular dynamic study of the OPG/RANKL system. Within the molecular models, we varied the number of OPG molecules bound to the RANKL trimer and carried out a study to determine how the binding affinity of the OPG/RANKL system changes as a function of OPG concentration. The molecular mechanics Poisson-Boltzmann surface area method was used to analyze binding free energies. It is shown that the binding affinity decreases with increasing numbers of OPG molecules. Additionally, conformational changes of RANKL, interactions between the N-terminus outlier module of OPG with RANKL, and residues that play an important role in the binding of OPG to RANKL trimer were investigated. A probable cause for unfavorable binding for a third OPG molecule was found. Along with the currently available experimental studies, this computational study will be valuable for the comprehensive understanding of OPG/RANKL at the atomistic level.