Coarse-Grained Simulation of Full-Length Integrin Activation

TC Bidone and A Polley and J Jin and T Driscoll and DV Iwamoto and DA Calderwood and MA Schwartz and GA Voth, BIOPHYSICAL JOURNAL, 116, 1000-1010 (2019).

DOI: 10.1016/j.bpj.2019.02.011

Integrin conformational dynamics are critical to their receptor and signaling functions in many cellular processes, including spreading, adhesion, and migration. However, assessing integrin conformations is both experimentally and computationally challenging because of limitations in resolution and dynamic sampling. Thus, structural changes that underlie transitions between conformations are largely unknown. Here, focusing on integrin alpha v beta(3), we developed a modified form of the coarse-grained heterogeneous elastic network model (hENM), which allows sampling conformations at the onset of activation by formally separating local fluctuations from global motions. Both local fluctuations and global motions are extracted from allatom molecular dynamics simulations of the full-length alpha v beta(3) bent integrin conformer, but whereas the former are incorporated in the hENM as effective harmonic interactions between groups of residues, the latter emerge by systematically identifying and treating weak interactions between long-distance domains with flexible and anharmonic connections. The new hENM model allows integrins and single-point mutant integrins to explore various conformational states, including the initiation of separation between alpha- and beta-subunit cytoplasmic regions, headpiece extension, and legs opening.

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