Blocker escape kinetics from a membrane channel analyzed by mapping blocker diffusive dynamics onto a two-site model

When a large solute molecule enters a membrane channel from the membrane-bathing electrolyte solution, it blocks the small-ion current flowing through the channel. If the molecule spends in the channel sufficiently long time, individual blockades can be resolved in single-channel experiments. In this paper, we develop an analytical theory of the blocker escape kinetics from the channel, assuming that a charged blocking molecule cannot pass through a constriction region (bottleneck). We focus on the effect of the external voltage bias on the blocker survival probability in the channel. The bias creates a potential well for the charged blocker in the channel with the minimum located near the bottleneck. When the bias is strong, the well is deep, and escape from the channel is a slow process that allows for time-resolved observation of individual blocking events. Our analysis is performed in the framework of a two-site model of the blocker dynamics in the channel. Importantly, the rate constants, fully determining this model, are derived from a more realistic continuum diffusion model. This is done by mapping the latter onto its two-site counterpart which, while being much simpler, captures the main features of the blocker escape kinetics at high biases.