Show Me Your Moves: a Comprehensive in Silico Analysis of the Dynamics of the CXCR4 Receptor

Current understanding of C-X-C chemokine receptor type 4 (CXCR4) activation relies on many crystal structures, which mostly represent a small fraction of this receptor’s conformational landscape. We performed extensive MD simulations of CXCR4 receptor to elucidate its dynamical behaviour. We updated previous CXCR4 activation model that shows H294 7.45 conformational rearrangement was not consistent with its role determined experimental mutagenesis by comparing the dynamical behaviour of two different models of CXCR4’s binding site, with H294 7.45 simulations either neutral or positively charged states. Positively charged H294 7.45 recovers the sodium binding site conformation observed in CXCR4 experimental structures and shows better agreement with in silico mutations than its neutral counterpart.