HMWK - Hessen Horizon: Marie Skłodowska-Curie-Postdoc Fellowship

Mechanics of the nuclear pore complex: from atomistic modelling to functional dynamics

In eukaryotic cells, the genetic material is contained within the nucleus, which is separated from the cytoplasm by the nuclear envelope. The nuclear pore complex (NPC) is located at the nuclear envelope and facilitates molecular transit between the nucleus and the surrounding cytoplasm. The ability of the NPC to maintain a dynamic structure is central to its function, as it responds to stress conditions with conformational changes and diameter fluctuations that affect transport. Understanding NPC structural dynamics requires atomistic detail and has implications for cellular function and disease. This project aims to develop mechanistic models of NPC dynamics using atomistic molecular dynamics (MD) simulations. I will simulate key NPC components (scaffold, luminal ring, permeability barrier) individually and collectively to propose a theoretical model for NPC diameter mechanoregulation and its interplay with nuclear transport. Cryo-electron tomography and fluorescence lifetime imaging will be used to validate and refine the model. This project will establish a computational pipeline for MD simulations applicable to diverse multi-protein complexes. In addition to introducing an approach to comprehensively explore biological phenomena at the atomic level by integrating diverse experimental data with physical models and computational simulations, this project sets a milestone for large-scale MD simulations. This highly interdisciplinary work, relying on the outstanding computational resources at the host institute and strong collaborations with renowned experimental groups, will advance our understanding of NPC dynamics and provide opportunities for future research as well as the potential development of novel therapeutics. Given its significance, timeliness, and broad applicability, it will in turn pave the way for my future career as an independent researcher.