First-Passage Time to Clear the Way for Receptor-Ligand Binding in a Crowded Environment

Certain biological reactions, such as receptor-ligand binding at cell-cell interfaces and macromolecules binding to biopolymers, require many smaller molecules crowding a reaction site to be cleared. Examples include the T-cell interface, a key player in immunological information processing. Diffusion sets a limit for such cavitation to occur spontaneously, thereby defining a time scale below which active mechanisms must take over. We consider N independent diffusing particles in a closed domain, containing a subregion with N_{0} particles, on average. We investigate the time until the subregion is empty, allowing a subsequent reaction to proceed. The first-passage time is computed using an efficient exact simulation algorithm and an asymptotic approximation in the limit that cavitation is rare. In this limit, we find that the mean first-passage time is subexponential, T∝e^{N_{0}}/N_{0}^{2}. For the case of T-cell receptors, we find that stochastic cavitation is exceedingly slow, 10^{9}  s at physiological densities; however, it can be accelerated to occur within 5 s with only a fourfold dilution.