Computational models of cell mechanosensing through integrin-based adhesions

Summary
Transmembrane adhesion proteins play an important role in molecular transport, signal
transduction, energy utilization and many other basic cellular functions. Their activity is
modulated by mechanical signals, that are typically sensed and transduced through changes in
conformation, function and biochemical interactions. Integrin transmembrane receptors respond
to mechanical forces from the microenvironment by changing conformation and ligand binding.
These changes regulate the assembly of adhesions between cells and the extracellular
environment and, in turn, control cell activity, including spreading and migration. However, the
molecular origin of these mechanisms remains largely elusive. The present research is focused
on determining the molecular origin of integrin mechanosensing and how it relates to cell motion
using multiscale modeling techniques. We will combine molecular dynamics simulations with
new coarse-graining methods and mesoscale stochastic approaches in order to identify the
conformational pathways underlying the responses of integrin to variations in the mechanics of
the microenvironment. Then, we will study how this conformational pathway regulates cell
motion. Results will reveal the molecular mechanisms underlying mechanochemical functions of
integrin, for future control of cells’ activity in several human pathologies.

Grant Number: 5R35GM147491-04
NIH Institute/Center: NIH
Principal Investigator: Tamara Bidone