Multiscale Simulation of Cadherin-Mediated Cell Adhesion

Abstract

Inter-cellular junctions play a pivotal role in the assembly of cells into specific three-dimensional tissues. Cadherins constitute a large family of Ca2+-dependent adhesion molecules that contain an N-terminal ectodomain, a transmembrane anchor and a C-terminal intracelluar region that contains highly conserved binding sites for catenin proteins which provide indirect links to the cytoskeleton. Although the molecular mechanisms underlying cadherin-mediated cell adhesion are still not fully understood, it seems likely that both cis dimers that are formed by binding of extracellular domains of two cadherins on the same cell surface, and trans-dimers formed between cadherins on opposing cell surfaces, play a role in junction formation.One difficulty that arises in studying any membrane-constrained process is that binding affinities are generally determined for molecules that are free in solution whereas the constraint of a membrane imposes a 2D environment on interacting molecules, for example for membrane-anchored receptors such as cadherins. Here we present a computational strategy to model the process of junction formation based on a knowledge of 3D binding affinities. The cell interfacial region is defined by a simplified system where each of two interacting membrane surfaces is represented as a two-dimensional lattice with each cadherin molecule treated as a randomly diffusing unit. The binding energy for a pair of interacting cadherins in this two-dimensional discrete system is obtained from 3D binding affinities through a renormalization process derived from statistical thermodynamics. The properties of individual cadherins used in the lattice model are based on molecular level simulations. Our results show that within the range of experimentally-measured binding affinities, cadherins condense into junctions driven by the coupling of cis and trans interactions. The key factor appears to be a decrease in the conformational freedom of trans dimers that increases the magnitude of lateral cis interactions.