Paper Citing NAMD - Abstract
Puklin-Faucher, Eileen; Gao, Mu; Schulten, Klaus; Vogel, Viola
How the headpiece hinge angle is opened: new insights into the dynamics of integrin activation
JOURNAL OF CELL BIOLOGY, 175:349-360, OCT 23 2006
How the integrin head transitions to the high-affinity conformation is debated. Although experiments link activation with the opening of the hinge angle between the beta A and hybrid domains in the ligand- binding headpiece, this hinge is closed in the liganded alpha(v)beta(3) integrin crystal structure. We replaced the RGD peptide ligand of this structure with the 10th type III fibronectin module (FnIII(10)) and discovered through molecular dynamics (MD) equilibrations that when the conformational constraints of the leg domains are lifted, the beta A/hybrid hinge opens spontaneously. Together with additional equilibrations on the same nanosecond timescale in which small structural variations impeded hinge-angle opening, these simulations allowed us to identify the allosteric pathway along which ligand- induced strain propagates via elastic distortions of the alpha 1 helix to the beta A/hybrid domain hinge. Finally, we show with steered MD how force accelerates hinge-angle opening along the same allosteric pathway. Together with available experimental data, these predictions provide a novel framework for understanding integrin activation.
