Mechanical Unbinding of Leukocyte Function-Associated Antigen-1 with ICAM-1 and ICAM-3 Complexes involves a Single Energetic Barrier

Abstract

Integrin belongs to a family of proteins that play crucial roles in both cell adhesion and signal transduction. Integrins on leukocytes (leukocyte function-associated antigen-1 or LFA-1) bind to intercellular adhesion molecules (ICAMs) to facilitate the adhesion and the migration of the cell to an inflammatory site. Recently, Moy et al. probed the unbinding of LFA-1 with ICAM-1 and ICAM-2 using AFM at the single-molecule level. They observed two separate regimes where the most probable unbinding force depended linearly on the logarithm of the loading rate and interpreted the two-regime behavior as the crossing of two free energy barriers. In the present work, we used coarse-grained Brownian Dynamics simulation to study the mechanical unbinding of LFA-1 from ICAM-1 and ICAM-3. We observed that the force-loading rate curves also displayed the fast and slow loading regimes, and the extracted kinetic parameters according to the Bell and Evans models were in quantitative agreement with those extracted from the experimental data. Moreover, employing the force-clamp mode, we found only a single energetic barrier and the two regimes resulted from an abrupt change in the transition state position. We expect similar results for the LFA-1/ICAM-2 complex, whose PDB structure is thought to be similar but not yet available.