Molecular Dynamics Simulations of Cell-Cell Adhesion Complexes

Marcos Sotomayor, University of Chicago

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Selective and robust adhesion between cells is essential for the development of complex multicellular organs and tissues. Classical cadherin proteins are responsible for calcium-mediated cell-cell adhesion and have been implicated in various biologically relevant processes such as neuronal connectivity and prevention of tumor cell propagation. More recently, classical members of the cadherin family of proteins have been shown to be functional mechanosensors. The main goal of this project is to use large-scale all-atom molecular dynamics simulations to establish the collective calcium-dependent response of multi-cadherin adhesion complexes (adherens junctions) to mechanical force.

Adherens junctions are formed by classical members of the cadherin superfamily, which typically have a cytoplasmic domain, a single-pass transmembrane domain, and five extracellular cadherin (EC) repeats. The EC repeats are arranged in series and linker regions between them feature highly conserved calcium-binding motifs. Cell-cell adhesion mediated by classical cadherins is achieved by interactions between their extracellular domains coming from adjacent cells (trans interaction). The interaction between extracellular domains of classical cadherins is calcium dependent and occurs in two steps through a so-called "X-dimer" binding interface and a subsequent tip-to-tip "strand-exchanged" bond. Biophysical experiments indicate that these trans interactions are weak at the level of single molecules, and that interactions among molecules protruding from the same cell (cis) are even weaker. Thus, the strength of classical cadherin-mediated adhesion comes about from the many cadherin molecules that co-localize and interact to form "adherens junctions." The molecular architecture of these junctions has been controversial, but recent structural studies support a view in which classical cadherins interact tip-to-tip in a periodic lattice that facilitates both trans and cis interactions. While the calcium-dependent dynamics and elastic response of single cadherin molecules have been experimentally and computationally probed, the dynamics of disassembly upon calcium depletion and the collective response to mechanical forces of multi-cadherin adhesion complexes remains unexplored.

Molecular dynamics simulations from our group and others have provided a unique dynamic view of how calcium ions control the shape, elasticity, and binding properties of single cadherin bonds. These simulations successfully reproduced known properties of classical cadherins, highlighted the relevance of an atomistic description of protein and ions, and provided novel predictions, some of which have been confirmed experimentally. Based on the available structures of adherens junctions and on the availability of petascale supercomputing systems for the simulations of large protein complexes, we now seek to use the same methodology to address a key question related to the function of multi-cadherin complexes: How does an adherens junction respond to calcium depletion and to mechanical force? Specifically, how are cis interactions, calcium ions, and the collective response of many cadherins responsible for the strengthening of adhesion and for signal transduction? Answers to these questions require atomistic simulations of systems encompassing > 2 million atoms, which in turn require the use of specialized software (NAMD) and extensive petascale computational resources, as uniquely provided by the Blue Waters supercomputer.