Alladi Ramakrishnan Hall

How does the closed state of αVβ3 Integrin destabilized by mutations? -Multiscale Molecular Dynamics Study

Anirban Polley

The University of Chicago, Illinois, USA

Integrins are transmembrane cell-surface molecules that act as primary
adhesion receptors for the extracellular matrix (ECM) and play critical roles
in cell-cell adhesion, cell migration, proliferation, and survival. Integrins
undergo tension-dependent conformational transitions correlated with
changes in binding affinity. Despite the importance of integrin conformation
in ECM binding, pathway of integrin activation remains elusive. Using
multiscale molecular dynamics modeling and simulation, we study the
conformation changes in wild type and mutant integrins and provide an
atomic-scale structural information for integrin intermediates. Our
simulation work shows that the integrin’s ectodomain moves away from the
membrane surface and the transmembrane helices from the two subunits of
integrin separate for mutant systems that stabilize open state. We finally
extend the scope of this study by applying essential dynamics coarse
graining and generating heterogeneious elastic network model from various
molecular structures of integrin mutants, proposing a multiscale modeling
framework for potential future studies of integrin aggregation and focal-
adhesion maturation.