Md Simulations On A Well-Built Docking Model Reveal Fine Mechanical Stability And Force-Dependent Dissociation Of Mac-1/Gpib Alpha Complex

Interaction of leukocyte integrin macrophage-1 antigen (Mac-1) to platelet glycoprotein Ib alpha (GPIb alpha) is critical for platelet-leukocyte crosstalk in hemostasis and inflammatory responses to vessel injuries under hemodynamic environments. The mechano-regulation and its molecular basis for binding of Mac-1 to GPIb alpha remain unclear, mainly coming from the lack of crystal structure of the Mac-1/GPIb alpha complex. We herein built a Mac-1/GPIb alpha complex model through a novel computer strategy, which included a flexible molecular docking and system equilibrium followed by a "force-ramp + snapback" molecular dynamics (MD) simulation. With this model, a series of "ramp-clamp" steered molecular dynamics (SMD) simulations were performed to examine the GPIb alpha-Mac-1 interaction under various loads. The results demonstrated that the complex was mechano-stable for both the high rupture force (>250 pN) at a pulling velocity of 3 angstrom/ns and the conformational conservation under various constant tensile forces (<= 75 pN); a catch-slip bond transition was predicted through the dissociation probability, examined with single molecular AFM measurements, reflected by the interaction energy and the interface H-bond number, and related to the force-induced allostery of the complex; besides the mutation-identified residues D222 and R218, the residues were also dominant in the binding of Mac-1 to GPIb alpha. This study recommended a valid computer strategy for building a likely wild-type docking model of a complex, provided a novel insight into the mechanical regulation mechanism and its molecular basis for the interaction of Mac-1 with GPIb alpha, and would be helpful for understanding the platelet-leukocyte interaction in hemostasis and inflammatory responses under mechano-microenvironments.