Simulations of cell-surface integrin binding to nanoscale-clustered adhesion ligands.

Clustering of ligated integrins strongly influences integrin signaling and mechanical linkages between integrins and intracellular structures. Extracellular spatial organization of integrin ligands in clusters may facilitate clustering of bound integrins and thus potentially regulate cellular responses to a defined average amount of ligand in the extracellular environment. The possible role of such ligand clustering effects in controlling overall receptor occupancy is studied here using a simple mass-action equilibrium model as well as a two-dimensional Monte Carlo lattice description of the cell-substrate interface, where cell surface receptors are free to diffuse in the plane of the interface and interact with the substrate-immobilized ligand. Results from the analytical treatment and simulation data indicate that for a single-state model in which receptor-ligand binding equilibria are not influenced by neighboring complexes, clustering of ligand does not enhance total receptor binding. However, if receptor binding energy increases in the presence of neighboring ligated receptors, strong ligand spatial distribution effects arise. Nonlinear responses to increasing ligand density are also observed even in the case of random ligand placement due to stochastic juxtaposition of ligand molecules. These results describe how spatial distribution of ligand presented by the extracellular matrix or by synthetic biomimetic materials might control cell responses to external ligands, and suggest a feedback mechanism by which focal contact formation might be initiated.