Utilizing Molecular Dynamics Simulations to Probe the Release of Signal Factors from the Adherens Junction

Abstract

The adherens junction (AJ) in epithelia is a ubiquitous cell-cell contact formed by classical members of the cadherin superfamily and a complex of cytoplasmic proteins that link the junction to the underlying cytoskeleton. The formation and maintenance of AJs are modulated by tension, and the AJ dynamically responds to changes in force from both extra- and intra-cellular structures. The cytoplasmic portion of epithelial cadherin (CDH1), the main cadherin of the junction, binds to and sequesters multiple cell-proliferation signaling molecules that act as linkers to the cytoskeleton. Here we present models of a complete and a minimal AJ based on available experimental and crystallographic data, and simulations of force mechanotransduction through the minimal AJ model. The models include CDH1, a phosphatidylcholine cell membrane, and the cytoplasmic proteins p120-catenin, β-catenin, α-catenin, vinculin, and F-actin. All the connections between protein pairs were modeled using available structures. Molecular dynamics simulations of the minimal AJ (∼2.88 M atoms), both with and without tension, allowed us to examine how simulated force applied to the junction alters the orientation and potential release of associated cytoplasmic proteins. Our simulations provide insight into the initial steps of tension-mediated signaling at the AJ.