Submitted by (Bold are A*Star Staff): Choon-Peng Chng,
Title of Paper:
Leukocyte integrin aLb2 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 a- and b-subunits, with each subunit consisting of a large ectodomain, a singlepass 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 aLb2 TMs that is absent in the platelet integrin aIIbb3 OMC. Here, we compare the self-assembly dynamics of aLb2 and aIIbb3 TM helices in a model membrane using coarse-grained molecular dynamics simulations. We found that although aIIbb3 TM helices associate more easily, packing is suboptimal. In contrast, aLb2 TM helices achieve close-to-optimal packing. This suggests that aLb2 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 aLb2 compared with aIIbb3. The aIIbb3 profile is also more rugged with energetic barriers whereas that of aLb2 is almost without barriers. Disruption of the interhelix hydrogen bond in aLb2 via the b2T686G mutation results in poorer association and a similar profile as aIIbb3. The OMC polar interaction in aLb2 thus plays a significant role in the packing of the TM helices.
Acknowledegment remark in publication: The authors thank the A*STAR Computational Resource Center for the generous allocation of computing time on the Axle and Fuji computer clusters.