Dynamics of β3 integrin I-like and Hybrid domains: Insight from simulations on the mechanism of transition between open and closed forms

The conformational dynamics of the I-like and Hybrid domains from the β3 integrin headpiece were studied by molecular dynamics simulation and normal mode analysis. Crystallographic structures of integrins show that the integrin headpiece can exist in largely different conformations manifested by a significant difference in the angle between the I-like and Hybrid domains. The relative orientation of these two domains is believed to be a crucial element of integrin function, as it may relate local structural modifications induced by ligand binding into large-scale conformational changes. To investigate the detailed mechanisms responsible for this coupling, we carried out molecular dynamics simulations of the I-like/Hybrid system and employed quasi-harmonic and normal mode analyses to characterize the large-scale motions. Our results show that the conformational transition of I-like and Hybrid domains inferred from crystallographic data is contained in the low-frequency dynamics of the system. Using targeted molecular dynamics simulations, we investigated the roles played by two structural elements of the I-like domain, the α7 and α1 helices, in the interdomain transition. From our results, we propose that these two helices function in tandem to initiate large-scale, interdomain conformational transition apparent in integrin activation and signaling.