Structural Insights into How the MIDAS Ion Stabilizes Integrin Binding to an RGD Peptide under Force

AbstractIntegrin αVβ3 binds to extracellular matrix proteins through the tripeptide Arg-Gly-Asp (RGD), forming a shallow crevice rather than a deep binding pocket. A dynamic picture of how the RGD-αVβ3 complex resists dissociation by mechanical force is derived here from steered molecular dynamic (SMD) simulations in which the major force peak correlates with the breaking of the contact between AspRGD and the MIDAS ion. SMD predicts that the RGD-αVβ3 complex is stabilized from dissociation by a single water molecule tightly coordinated to the divalent MIDAS ion, thereby blocking access of free water molecules to the most critical force-bearing interaction. The MIDAS motif is common to many other proteins that contain the phylogenetically ancient von Willebrand A (vWA) domain. The functional role of single water molecules tightly coordinated to the MIDAS ion might reflect a general strategy for the stabilization of protein-protein adhesion against cell-derived forces through divalent cations