Modeling Polymer-Coated Nanopores in Nature and Nanotechnology

University Of Pittsburgh, Pittsburgh PA

Investigators

Abstract

Rob Coalson of the University of Pittsburgh is supported by an award from the Chemical Theory, Models and Computational Methods program in the Division of Chemistry to carry out computational modeling of polymer-coated nanopores in nature and nanotechnology. The primary inspiration for this work is the Nuclear Pore Complex (NPC), a large protein complex that perforates the nuclear envelope in eukaryotic cells and serves as the sole conduit of small and large biomolecules into and out of the cell nucleus. The NPC is comprised of natively unfolded protein filaments (nucleoporins) which extend from the pore wall into its center. These filaments form a tight barrier to the transport of random biomolecules through the pore. Hydrophobic (water-hating) segments on the nucleoporins bind transiently to hydrophobic groves on certain globular receptor proteins (Nuclear Transport Factors [NTFs]). These NTFs can simultaneously bind cargo molecules earmarked for flow into or out of the nucleus. Upon binding to the NTFs, cargos are ferried through the NPC pore due to the interactions between the NTFs and the nucleoporin chains that line the pore. The Coalson group seeks to clarify critical details of the transport process using coarse-grained computer models, which are appropriate due to the imposing size and scale of the NPC. At the same time, the efficiency of the NPC’s operation in vivo inspires the construction of synthetic polymer-coated nanopores that function as molecular sieves, based on the size and chemical composition of the molecules filtered through them. The Coalson group will pursue these applications as well. Defects in Nuclear Pore Complexes result in serious maladies, including cancer and numerous infectious diseases. The relevance of NPC nanopores to human physiology suggests that this research may ultimately contribute to improvement of human health, e.g., via the development of pharmaceutical agents that correct for their malfunction. Within the research group, biological nanopore research is carried out synergistically with teaching and outreach activities, which include running an intramural (University of Pittsburgh) seminar series on Biophysical Theory, and creation and implementation of NSF-funded Summer Institutes focused on computational biology for undergraduate and graduate students. These efforts contribute to education in biological nanopore science and, more generally, molecular biophysics, over a wide range of career stages and pathways: from undergraduates to senior researchers (natural scientists, engineers and medical doctors). In addition, the research on synthetic nano-devices, such as polymer coated nanopores, has implications for nano-technology and nano-medicine. The Coalson group elucidates nanopore structure-function relations by developing novel physico-chemically grounded coarse-grained simulation models combined with creative statistical mechanical analysis that includes Flory-Huggins models and self-consistent field theory approximations. These tools enable the study of larger systems and longer time scales than can be accessed by all-atom Molecular Dynamics simulations, namely, mesoscopic scales where the collective behavior of many large molecules impacts the pore's ability to select molecular cargos to pass through it. Details of the NPC structure and transport mechanism inspire the construction of synthetic nanoscale motifs in which (non-biological) polymer molecules are grafted to the inside of a cylindrical scaffold, and then polymer collapse transitions are exploited to open and close these nanovalves, thus enabling them to be used for size-selective sieving of analyte molecules. Polymer morphology changes can be controlled by the infiltration of specialized nanoparticles, which are introduced into solution in appropriate amounts. In a similar vein, the Coalson group designs polymer-coated nanoballs (e.g., spherical colloid particles) that stick preferentially to specific surfaces within the relevant flow space (e.g., a biological cell). The ultimate goal here is to develop nanoscopic directed delivery devices, with appropriate payload molecules being contained within the nanoball. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.