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Cell adhesion complexes (CACs), which are activated by ligand binding, playkey roles in many cellular functions ranging from cell cycle regulation tomediation of cell extracellular matrix adhesion. Inspired by single moleculepulling experiments on leukocyte function-associated antigen-1 (LFA-1),expressed in T-cells, bound to intercellular adhesion molecules (ICAM), weperformed constant loading rate ($r_f$) and constant force ($F$) simulationsusing the Self-Organized Polymer (SOP) model to describe the mechanism ofligand rupture from CACs. The simulations reproduce the major experimentalfinding on the kinetics of the rupture process, namely, the dependence of themost probable rupture forces ($f^*$s) on $\ln r_f$ ($r_f$ is the loading rate)exhibits two distinct linear regimes. The first, at low $r_f$, has a shallowslope whereas the slope at high $r_f$ is much larger, especially forLFA-1/ICAM-1 complex with the transition between the two occurring over anarrow $r_f$ range. Locations of the two transition states (TSs), extractedfrom the simulations show an abrupt change from a high value at low $r_f$ or$F$ to a low value at high $r_f$ or $F$. The unusual behavior in which the CACsswitch from one brittle (TS position is a constant over a range of forces)state to another brittle state is not found in forced-rupture in other proteincomplexes. We explain this novel behavior by constructing the free energyprofiles, $F(\Lambda)$s, as a function of a collective reaction coordinate($\Lambda$), involving many key charged residues and a critical metal ion. TheTS positions in F($\Lambda) change abruptly at a critical force, demonstratingthat it, rather than the molecular extension is a good reaction coordinate. Wereveal a new mechanism for the two loading regimes observed in the rupturekinetics in CACs.

Forced-rupture of Cell-Adhesion Complexes Reveals abrupt switch between two Brittle States