Stochastically gated diffusion model of selective nuclear transport

Abstract

Nuclear pore complexes (NPCs) allow the selective exchange of molecules between the cytoplasm and cell nucleus. Although small molecules can diffuse freely through a NPC, the transport of proteins and nucleotides requires association with transport factors (kaps). The latter transiently bind to disordered flexible polymers within the NPC, known collectively as phenylalanine-glycine-nucleoporins (FG-Nups). It has recently been shown that transient binding combined with diffusion in the bound state is a sufficient mechanism for selective transport. However, selectivity is significantly reduced if the mobility of the bound state is too slow. In this paper we formulate the binding-diffusion mechanism of selective transport in terms of a "stochastically gated" diffusion process in which each bound particle undergoes confined diffusion within a subdomain of the NPC. This allows us to make explicit the fact that the diffusion of a particle when bound to a polymer tether is spatially confined rather than simply reduced. We calculate the selectivity of the NPC and explore its dependence on the size of the confinement domains. We then use probabilistic methods to determine the splitting probability and mean first passage time (MFPT) for an individual particle to pass through the pore. Our analysis establishes that spatial confinement can significantly reduce selectivity in a binding-diffusion model, suggesting that other biophysical mechanisms such as interchain transfer are required.