Transforming binding affinities from three dimensions to two with application to cadherin clustering
Open Access
- 27 July 2011
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature
- Vol. 475 (7357), 510-513
- https://doi.org/10.1038/nature10183
Abstract
Relating the strengths of interactions occurring in two dimensions on membrane surfaces to those measured in three dimensions in solution is a perennial problem in cell biology. Barry Honig and colleagues use a computational and theoretical approach that enables a new type of structurally- and biophysically-driven analysis of processes that occur on cell surfaces. Applying this approach to cadherin-mediated cell adhesion reveals novel principles about how cell–cell interactions drive receptor clustering on membrane surfaces. Membrane-bound receptors often form large assemblies resulting from binding to soluble ligands, cell-surface molecules on other cells and extracellular matrix proteins1. For example, the association of membrane proteins with proteins on different cells (trans-interactions) can drive the oligomerization of proteins on the same cell2 (cis-interactions). A central problem in understanding the molecular basis of such phenomena is that equilibrium constants are generally measured in three-dimensional solution and are thus difficult to relate to the two-dimensional environment of a membrane surface. Here we present a theoretical treatment that converts three-dimensional affinities to two dimensions, accounting directly for the structure and dynamics of the membrane-bound molecules. Using a multiscale simulation approach, we apply the theory to explain the formation of ordered, junction-like clusters by classical cadherin adhesion proteins. The approach features atomic-scale molecular dynamics simulations to determine interdomain flexibility, Monte Carlo simulations of multidomain motion and lattice simulations of junction formation3. A finding of general relevance is that changes in interdomain motion on trans-binding have a crucial role in driving the lateral, cis-, clustering of adhesion receptors.This publication has 23 references indexed in Scilit: