Mechanochemical mechanism of integrin clustering modulated by nanoscale ligand spacing and rigidity of extracellular substrates.

Experimental findings indicate that cell function and behavior such as cell growth, division, migration and differentiation, are subtly regulated via integrin-dependent cell adhesion. Cell adhesion is influenced by nanoscale ligand spacing and rigidity of extracellular substrates, as cell adhesion drops greatly when the ligand spacing is larger than ~60nm, and cell adhesion is stronger on stiff than soft substrates. However, how nanoscale ligand spacing and substrate stiffness jointly affect integrin clustering and hence nascent cell adhesion remains to be elucidated. To quantitatively investigate the phenomena and the underlying mechanochemical mechanism of integrin clustering modulated by ligand spacing and substrate stiffness, we introduced Monte Carlo simulations varying the values of ligand spacing and substrate stiffness. Moreover, the effects of integrin number, integrin binding free energy, integrin association free energy, and local ligand spacing were investigated. The simulation results showed that integrin clustering decreased sharply, when ligand spacing was relatively large such as d>60nm in the current simulations, regardless of substrate rigidities, though with close spacing, the clustering increased with the substrate stiffness. The investigation contributes to the goals of understanding and predicting experimental phenomena, directing and optimizing biomaterial design, and manipulating integrin-dependent cell-substrate adhesion in tissue engineering.