Before the First Bond: Depletion-Assisted Stochastic Capture at the Onset of Endocytosis

Abstract

In a crowded extracellular environment, viruses and nanoparticles must reach the cell membrane within a few nanometers before the first ligand-receptor bond can form. Crowders generate an entropic depletion attraction, yet continuum models usually assume contact is already established or treat the approach deterministically. We formulate a thermodynamically consistent stochastic theory for this pre-contact stage. The sphere-plane depletion geometry uses the exact Asakur-Oosawa spherical-cap overlap, rather than a fitted cap, with either ideal van 't Hoff or pressure-only Carnahan-Starling osmotic pressure. A spatially varying near-wall mobility introduces a noise-induced drift that is essential for thermodynamic consistency and is often omitted. The first specific reaction is modeled by a Robin radiation boundary; the outer boundary is reflecting or absorbing. Three first-passage problems are solved analytically by quadrature: the mean reaction time, the reaction-before-escape probability, and the conditional success time, the last encoded by a Doob transform that exposes the selection bias of conditioning on capture. The theory separates thermodynamic inputs from conditional parameters and reveals a reaction-limited to diffusion-limited crossover controlled by the local Damköhler number. For typical virus and nanoparticle parameters, the depletion well reaches $2$-$6\,k_{\rm B}T$, capture times are $0.1$-$1\,{\rm ms}$, and the conditional success time is measurably shorter than the unconditional mean. Finite-volume and Chebyshev schemes reproduce the analytic results within their discretization errors and satisfy the radiation-boundary mass balance. This provides a quantitative theoretical framework for crowding-assisted capture prior to membrane wrapping and a reference for comparing crowding, near-wall mobility, and surface reactivity in endocytosis.