  Cell adhesion complexes (CACs), which are activated by ligand binding, play
key roles in many cellular functions ranging from cell cycle regulation to
mediation of cell extracellular matrix adhesion. Inspired by single molecule
pulling experiments on leukocyte function-associated antigen-1 (LFA-1),
expressed in T-cells, bound to intercellular adhesion molecules (ICAM), we
performed constant loading rate ($r_f$) and constant force ($F$) simulations
using the Self-Organized Polymer (SOP) model to describe the mechanism of
ligand rupture from CACs. The simulations reproduce the major experimental
finding on the kinetics of the rupture process, namely, the dependence of the
most 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 shallow
slope whereas the slope at high $r_f$ is much larger, especially for
LFA-1/ICAM-1 complex with the transition between the two occurring over a
narrow $r_f$ range. Locations of the two transition states (TSs), extracted
from 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 CACs
switch 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 protein
complexes. We explain this novel behavior by constructing the free energy
profiles, $F(\Lambda)$s, as a function of a collective reaction coordinate
($\Lambda$), involving many key charged residues and a critical metal ion. The
TS positions in F($\Lambda) change abruptly at a critical force, demonstrating
that it, rather than the molecular extension is a good reaction coordinate. We
reveal a new mechanism for the two loading regimes observed in the rupture
kinetics in CACs.
