Leukocyte integrin αLß2 transmembrane association dynamics revealed by coarse-grained molecular dynamics simulations.

Integrins are transmembrane (TM) proteins that mediate bidirectional mechanical signaling between the extracellular matrix and the cellular cytoskeletal network. Each integrin molecule consists of non-covalently associated α- and ß-subunits, with each subunit consisting of a large ectodomain, a single-pass TM helix, and a short cytoplasmic tail. Previously we found evidence for a polar interaction (hydrogen bond) in the outer membrane clasp (OMC) of the leukocyte integrin αLß2 TMs that is absent in the platelet integrin αIIß3 OMC. Here, we compare the self-assembly dynamics of αLß2 and αIIß3 TM helices in a model membrane using coarse-grained molecular dynamics simulations. We found that although αIIß3 TM helices associate more easily, packing is suboptimal. In contrast, αLß2 TM helices achieve close-to-optimal packing. This suggests that αLß2 TM packing is more specific, possibly due to the interhelix hydrogen bond. Theoretical association free energy profiles show a deeper minimum at a smaller helix-helix separation for αLß2 compared with αIIß3. The αIIß3 profile is also more rugged with energetic barriers whereas that of αLß2 is almost without barriers. Disruption of the interhelix hydrogen bond in αLß2 via the ß2T686G mutation results in poorer association and a similar profile as αIIß3. The OMC polar interaction in αLß2 thus plays a significant role in the packing of the TM helices.