Molecular Dynamics Simulation Study on Allosteric Regulation of CD44-Hyaluronan Binding as a Force Sensing Mechanism.

CD44 protein exists on surfaces of a variety of human cells, acts as a receptor for the hyaluronan (HA) molecule, and mediates cell adhesion via the HA binding in leukocyte trafficking, cell rolling, and so on. The molecular structures of both CD44 and HA are well known, and the previous work shows that the external-mechanical force induces the partially disordered (PD) conformation from the ordered (O) conformation of CD44. The PD conformation has the higher HA affinity compared to the O conformation. However, the details of force-sensing mechanics have remained unclear. This study provides new insights into allosteric regulation of HA binding by conformational shift from the O to the PD conformation of the CD44 HA binding domain by using the classical molecular dynamics simulations. The O conformation was more favorable than the PD conformation under the equilibrium state, and the O conformation showed weak HA-binding affinity. Our simulation suggests that the PD conformation induced by the external force can refold to a compact structure similar to the O conformation keeping the bound HA. This new conformation showed a higher affinity than the O and PD conformations. Our results show that the unfolding of a remote disordered region from the ligand binding site by the external force allosterically regulates the HA affinity. This study promotes understanding not only the mechanism of CD44-mediated cell rolling but also the allosteric regulation induced by the external mechanical force.