Biophysical Society Thematic Meeting | Hamburg 2022

Biophysics at the Dawn of Exascale Computers

Wednesday Speaker Abstracts

STRUCTURE AND FUNCTION OF INTEGRIN: FROM MOLECULAR DYNAMICS TO ADHESION ASSEMBLY Tamara C Bidone 1 ; 1 University of Utah, Biomedical Engineering, Salt Lake City, UT, USA Integrin is a transmembrane adhesion protein that undergoes long range conformational transitions associated with its functional conversion from inactive (low affinity) to active (high affinity). Its inactive/bent and active/extended conformations have been described, however interconversion between these conformations necessarily involves intermediate states that are less well studied. Elucidating the properties of these intermediates at the atomistic level and characterizing their contributions to the assembly of adhesions at the mesoscale is important for understanding how cells form adhesions with the extracellular environment, change shape, and move. My lab develops algorithms that combine molecular simulations, analysis of the principal components of the atomistic motions, and mesoscale modeling to understand how integrin conformations govern the assembly of cell adhesions. Our studies reveal that the structural deformations of the bent and intermediate conformations are directed towards elongation of the headpiece away from the legs, and destabilization of the transmembrane helices; the open state presents high flexibility, with correlated motions between headpiece and legs. At the mesoscale, bent integrins cannot form stable adhesions, but intermediate or open conformations stabilize the adhesions. These effects are due to small variations in ligand binding affinity and ligand-bound lifetime in the presence of actin retrograde flow. Collectively, our results demonstrate how integrin receptors stabilize nascent adhesions through changes in atomistic motions that underlie differences in conformation, ligand-binding affinity, and ligand- bound lifetime. These findings are conceptually important because they identify new functional relationships between integrin conformation and cell function.

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