Mechanics of Cadherin Unbinding using Coarse-Grained Models

Abstract

Cell-cell adhesion is mediated by calcium-dependent proteins called cadherins, which are important in neuronal connectivity and tissue integrity. Cadherins are modular proteins with large extracellular domains that have typically been modeled using all-atom molecular dynamics (MD) simulations. However, these simulations are computationally expensive and most of them only include small fragments of these cadherin extracellular domains. To overcome these limitations, we used a coarse-grained (CG) model with the MARTINI force field to study large cadherin complexes over long time scales. All-atom MD simulations were used to find optimal parameters for an elastic network model that stabilized the protein secondary structure. The CG model allowed for a 5x increase in timestep and a 10-fold reduction of system sizes. Using this model we studied the dynamics and elastic response of classical cadherins and clustered protocadherins. In these simulations, the extracellular domains of classical cadherins straightened before unbinding, while protocadherins slipped past each other during unbinding. Overall, our results confirm that our model is an effective simulation tool for studying of the mechanics of cadherin complexes.