Biophysics of biological transport and signaling "nanomachines": from theory to applications

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The functioning of living cells relies on a multitude of molecular transport and signaling "biomachines". The principles of function of these natural biomachines - that have been optimized by evolution - guide the creation of artificial biomimetic devices and nanomaterials for nano- and bio-technology applications. This proposal focuses on a "nanomachine" known as the Nuclear Pore Complex (NPC), and the related biomimetic devices and biomaterials. NPC coordinates and gates the macromolecular transport between the cell nucleus and the cytoplasm by selectively transporting specific macromolecular complexes while efficiently filtering others. Equally importantly, it is involved in the maintenance of precise spatio-temporal partitioning of macromolecules between the nucleus and the cytoplasm by concentrating cargoes against their concentration gradients via the non-equilibrium between energy input through chemical reactions coupled to the transport process. NPC is an unusually large transporter with a complex internal organization. The key component of its functional mechanism is the assembly of the polymer-like intrinsically disordered proteins that fill its transport channel and dictate the specificity and the throughput of transport. Unlike many other molecular transporters, NPC transport is massively parallel, and its channel is crowded by hundreds of cargo-carrying transport proteins of multiple types traversing it in both directions. It still remains a puzzle how NPC maintains high throughput and selectivity without clogging under such crowded conditions. Furthermore, so far much of the biophysical investigations of the NPC and its constituents focused on the molecular physics of translocation and the biophysics of the NPC constitutes. By contrast, it remains unclear how the complex nano-scale architecture and dynamics work in concert with the non-equilibrium energy consumption mechanisms to generate molecular gradients that are robust with respect to molecular perturbations and noise. Theoretical and computational methods have proven to be indispensable  in the study of the NPC. Despite its complexity, many aspects of NPC structure and function can be understood from fundamental physical principles. Accordingly, many properties of the NPC function have been recapitulated in nanochannel mimics, providing validation of theoretical models. However, a few puzzles and open questions still remain. The goal of this proposal is to close these gaps in our quantitative understanding of the NPC, to lay the foundation for the understanding of various health and disease processes and to guide the rational design of biomimetic devices. In the process, this research will address several fundamental physical questions, such as multi-species phase separation in nano-confinement, mechanisms of molecular transport through complex molecular assemblies, and the coupling of equilibrium and non-equilibrium processes on the nanoscale.