These three fractions of bond states give rise to the LFA-1/ICAM-1 catch bond behavior in which the bond lifetimes are prolonged by Dabrafenib tensile force in a certain regime. Building from the above studies, we used steered molecular dynamics simulations with explicit water to study the forceinduced transitions of conformations of the LFA-1 aA domain. We also constructed a mathematical model to describe the interstate transitions integrin and their coupling with ligand dissociation. Using this model, we re-analyzed our previous data on single LFA1/ICAM-1 bonds lifetimes measured from biomembrane force probe force-clamp experiments, and estimated interstate transition rates that govern the time courses for activation of the liganded LFA-1 under force. To study the force-induced conformational transitions of the LFA-1 aA domain, we used constant-force SMD simulations to pull the C-terminus of its a7-helix, as the position of the tensionbearing a7-helix determines the aA domain conformation. Unlike the previous implicit water simulations, our simulations included physiologically relevant water molecules. To observe the sequential transitions of the a7-helix position, we quantified the root mean square distance between the simulated structure and its initial “up” position, which corresponds to the “closed” conformation of the aA domain. Pulling the a7-helix C-terminus in the first 3.6 ns only increased the RMSD slightly, indicating the stability of the “up” position. A sudden increase of the RMSD from 3 to 6 A˚ was then observed during 3.4–4 ns simulations, suggesting state transitions. Zooming in this transition phase with a magnified time scale, a stable “intermediate” a7-helix position with a 4.5-A˚ RMSD was observed. This “intermediate” a7- helix position is linked to the “intermediate” conformation of the aA domain. After two abrupt increments, the RMSD was stabilized at around 8 A˚ for the next 10 ns, corresponding to a “down” position of the a7-helix and the “open” conformation of the aA domain. After the pulling force was removed at the 15 ns time point, the a7-helix returned back from the “down” position to the “up” position in a few nanoseconds and remained up within the next 20-ns simulations. Besides the a7-helix position, another remarkable difference between the open and closed conformation of LFA-1 aA domain revealed by structural studies is the metal ion position at the metal ion dependent adhesion site. It was observed that in the open conformation, the MIDAS metal ion underwent inward movement for about 2 A˚. Previous implicit water molecular dynamics simulations suggested that the movement of a7-helix and that of the MIDAS metal ion were coupled. Hence, we measured the RMSD of the MIDAS metal ion and other important residues between the simulated structures and the open or closed conformations. These included residues S139, S141, T206, and D239 that coordinated the MIDAS metal ion and residues L289, F292, and L295 that formed a “ratchet”-like structure to define the position of the a7-helix.