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 beta 3 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 alpha 7 and alpha 1 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.