Mathematical Biology Seminar Tamara Carla Bidone, Department of Bioengineering, University of Utah Wednesday, October 3, 2019 3:05pm in JWB 335 Cell adhesions as mechanosensors: insights from multiscale computational models Abstract: The mechanisms by which cells form adhesions on substrates are critical to physiological and pathological processes, including wound healing, cancer metastasis and fibrosis. Cell adhesions are specialized membrane compartments that create physical links between external and intracellular environments. Integrin transmembrane proteins are the most important components of cell adhesions, with key roles in sensing and transmitting chemical and mechanical cues. Integrins respond to changes in substrate stiffness by forming different number of adhesions and changing the levels of transmitted stresses. However, the effects of substrate stiffness on integrin conformation and function remain elusive because of limitations in experimental resolutions. Computational modeling offers a powerful tool to study structure and function of individual proteins, as well as biological processes involving multiple proteins, such as the assembly of integrin-based adhesions. My lab develops multiscale computational models of biological systems and one of our projects is studying the structure and function of integrins. Our multiscale models of integrin have been used to understand the effect of mechanical tension on the protein conformation and on the assembly of integrin-based adhesions. We combined molecular dynamics simulations with coarse-grained modeling approaches and algorithms based on Brownian Dynamics in order to identify the conformational pathway of integrin activation and the formation of cell adhesions on substrates with different rigidities. Our results have allowed identifying tension-bearing domains of integrin, providing new structures along the conformational pathway of integrin extension under tension. Moreover, our models have allowed to demonstrate that integrin activity, in terms of substrate binding and adhesions lifetime, is determined by mechanical tension. By providing important insights into the molecular and macromolecular determinants of stiffness sensing and adhesions formation in cells, our models have shown that integrin is a cell mechanosensor.