Second, the previously proposed allosteric mechanism for the LFA-1/CHIR-99021 ICAM-1 catch-slip bond can be fully accounted for using the newly evaluated intrinsic parameters. Indeed, although the force-dependent dissociation of ICAM-1 from each of the three states behaves as slip bonds, force accelerates transition from C1 to C2 more than it does dissociation from C1 to R+L. Force also increases transition rate k23 from C2 to C3 comparably to it does dissociation rate kr2 from C2 to R+L. This interplay between force-accelerated interstate transition and dissociation gives rise to the LFA-1/ICAM-1 catch bond at low forces and slip bond at higher forces, as observed experimentally. Third, our model reveals that XVA143 suppresses the transition from C1 to C2 and inhibits the transition from C2 to C3 without altering the intrinsic reverse-rates kr1–kr2 for dissociation from the three LFA-1/ICAM-1 bond states. This result has elucidated the mechanism for XVA143 to covert the LFA-1/ICAM-1 catch-slip bond to slip-only bond. Because both interstate transitions are induced by force, our data indicate that XVA143 significantly weakens the force transmission from the aA to bA domains by blocking the binding of the intrinsic ligand of the aA domain a7-helix to the bA domain MIDAS. This finding supports the hypothesis that the three-state dissociations of LFA-1/ICAM-1 bonds are tightly regulated by the three-conformation transition of the LFA-1 aA domain. Fourth, the new model has allowed us to estimate the time scale for integrin activation by force. Integrin activation has been suggested to be almost instantaneous, but data from different experiments are variable. Binding of fluorochrome-labled ligands to integrin aIIbb3 reveals fast reversible formation of an integrin/ligand precomplex followed by a stable irreversible complex, during which the affinity upregulation occurs in a time scale of 10 seconds. Conversion from selectin-mediated rolling to integrin-mediated firm adhesion of leukocytes on endothelium and the detachment followed thereafter are used as criteria for integrin activation and deactivation. Chemokine-triggered full activation of LFA-1 mediates arrest of rolling lymphocytes on high endothelial venules within 1 second under flow conditions similar to those in the circulation. The conversion of rolling to stationary adhesion after the initial attachment of a neutrophil is induced by IL-1 in as little as 0.24 s in the presence of 1 dyn/cm2 shear stress. Force has been shown to facilitate the affinity upregulation at the cellular level. Our work provided the first estimates at the single-molecule level for the time scales of forceinduced integrin activation from the reciprocal interstate transition rates, 1/k12 and 1/k23, which range from tens of milliseconds to several seconds. Thus, the activation times estimated herein are in accordance with the previous reports. In addition, the interstate transition rates increase with increasing force, indicating that force accelerates LFA-1 activation.