Role of pore dilation in molecular transport through the nuclear pore complex: Insights from polymer scaling theory

The nuclear pore complex (NPC), a channel within the nuclear envelope filled with intrinsically disordered proteins, regulates the transport of macromolecules between the nucleus and the cytoplasm. Recent studies have highlighted the NPC’s ability to adjust its diameter in response to the membrane tension, underscoring the importance of exploring how variations in pore size influence molecular transport through the NPC. In this study, we investigated the relationship between pore size and transport rate and proposed a mathematical model describing this connection. We began by theoretically analyzing how the pore size scales with the characteristic dimensions of the mesh-like structure within the pore. By introducing key assumptions about how the meshwork structure influences molecular diffusion, we derived a mathematical expression for the transport rate based on the size of the pore and the transported molecules. To validate our model, we conducted Brownian dynamics simulations using a coarse-grained representation of the NPC. These simulations, performed across a range of pore sizes, demonstrated strong agreement with our model’s predictions, confirming its accuracy and applicability. Our model is specifically tailored for small-to-medium-sized molecules, approximately 5 nanometers in size, making it relevant to a wide range of transcription factors and signaling molecules. It also extends to molecules with weak and transient interactions with FG-Nups, such as importin-β. By presenting this model formula, our study offers a quantitative framework for analyzing the effects of pore dilation on nucleocytoplasmic transport.Author summary: Recent research has suggested the role of the NPC dilation in enhancing molecular flux, noting that increased nuclear membrane tension can widen the NPC and promote the nuclear entry of certain transcription factors. Despite observations that NPC dilation can be experimentally induced, structural analyses reveal that NPC diameter variations are limited, typically ranging from 40 to 60 nm. This raises the question of whether such modest changes in pore size can effectively influence molecular flux. Our study addresses this by demonstrating an exponential relationship between pore size and transport rate, indicating that even minor adjustments in pore size can substantially increase molecular flux by several orders of magnitude. This result emphasizes the critical impact of pore size on molecular transport, highlighting the significance of controlling the NPC geometry for cellular functions.