Abstract
<jats:p> 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 <jats:sup>7.45</jats:sup> 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 <jats:sup>7.45</jats:sup> simulations either neutral or positively charged states. Positively charged H294 <jats:sup>7.45</jats:sup> recovers the sodium binding site conformation observed in CXCR4 experimental structures and shows better agreement with in silico mutations than its neutral counterpart. </jats:p>