Eukaryotic cells possess a nucleus which is isolated from the cell's cytoplasm by the nuclear envelope. Nature requires a mechanism for selective inward/outward transport of proteins, mRNA, etc. This is enabled by protein nano-pores known as Nuclear Pore Complexes (NPCs) which span the nuclear envelope and allow controlled passage of physiologically essential molecules. Malfunction of NPCs is implicated in maladies such as cancer, cardiac disease and numerous infectious diseases; therefore, understanding the basic biophysical and biochemical aspects of the NPC transport cycle is an important first step in devising corrective therapies. Moreover, the ability of NPCs to permit passage of select bio-molecules suggests possible technological application as a nano-sieve allowing precise chemical separation at the nanometer scale.
Based on electron cryo-microscopy data, a rough structural characterization of these protein complexes has emerged. The diameter of the NPC pore is ca. 40 nm. The width of the nuclear envelope is ca. 50 nm, but the NPC architecture extends into both cytosolic and nuclear solutions, bringing its total length perpendicular to the membrane to ca. 150 nm. Not only are NPCs huge, but their physiological functions are extensive and complicated. One particularly important NPC structural component is comprised of nuclear pore proteins (nucleoporins, or "nups") that contain natively unfolded domains rich in phenylalanine-glycine (FG) repeats. These FG-nups behave as polymer strands that form a grafted brush extending out from the rim of the cylindrical pore into the interior. This cylindrical polymer brush motif appears to largely occlude the center of the cylindrical pore.
Various hypotheses have been proposed to explain the role of unfolded nup filaments in transport of large molecular cargos through the NPC pore. Important issues include: i) How can large cargos pass through the pore if it is occluded by nup filaments and ii) How does the pore selectively pass certain large cargo molecules while preventing the passage of others? The answers to these questions involve special transport receptor proteins that bind to a specific cargo molecule. The receptor proteins also have attractive interactions with nup monomers, generated by hydrophobic contacts between these two moieties. Thus the receptor-cargo complex can bind to the nup filaments, which encourages transport through the pore. In the absence of the receptor protein, a large cargo molecule is repulsed from entering the pore of the NPC due to blockage by nup filaments. Beyond these basic points, however, there is at present no consensus on the mechanism of assisted transport of cargo molecules through the NPC pore.
Given the complexity of the NPC system, a range of approaches are needed to unlock its secrets, including experimental measurements of structure-function relations in NPCs and NPC mimetic systems, and theoretical/computational investigations. Atomistic Molecular Dynamics (MD) will play an important role in computational studies, particularly in unlocking chemical details of the mechanism of NPC operation. Such calculations complement coarse-grained simulations, which focus on basic polymeric properties of the unfolded protein chains grafted to the inside of the NPC pore, and approximate statistical mechanical models (e.g., mean field theories), which can provide insight into the various simulations.
Furthermore, as mentioned above, the NPC architecture bears an intriguing resemblance to artificial nanopore systems that involve polymer filaments grafted to the inside of the pore (polymer brushes). "Smart" polymer brushes, whose properties are tunable via control parameters such as solution pH, temperature, or solute composition, show promise as components of nano-scale devices associated with electronics, optics, chemical detection and molecular sieving. Clearly, there is an enticing opportunity here to connect the fields of NPC biophysics and smart materials design.
Hence we propose to bring together 20-25 active researchers drawn from the fields of NPC structure-function relations and synthetic nanopore materials science for a Telluride Workshop on Nuclear Pore Complexes and Smart Polymers. We will invite both experimentalists and theoretician/simulators. The admixture of theory and experiment, as well as applications to biological NPCs, NPC mimetic systems, and synthetic polymer-based nanopores will lead to stimulating discussions, extensive cross-fertilization, and, ultimately, to significant advances in these fields.
We wish to ensure an intimate workshop setting, with no more than 20 to 25 participants. If you are interested in attending, but have not received an invitation, please contact the workshop organizer before registering. If you have registered for a meeting you were not invited to, you may be subject to a $100 fee.
TSRC is about expanding the frontiers of science, exploring new ideas, and building collaborations. The workshop schedule will allow for substantial unstructured time for participants to talk and think. All participants are expected to stay for the entire duration of the workshop.
Telluride Intermediate School
725 West Colorado Ave Telluride, CO 81435