Modeling Polymer-Coated Nanopores in Nature and Nanotechnology

匹兹堡大学的Rob Coalson获得了化学系化学理论，模型和计算方法计划的奖项，以进行自然界和纳米技术中聚合物涂层纳米孔的计算建模。 这项工作的主要灵感来自于核孔复合物（NPC），这是一种大型蛋白质复合物，可穿透真核细胞的核膜，并作为小型和大型生物分子进出细胞核的唯一管道。 NPC由天然未折叠的蛋白丝（核孔蛋白）组成，这些蛋白丝从孔壁延伸到其中心。 这些细丝对随机生物分子通过孔的运输形成紧密的屏障。 核孔蛋白上的疏水（憎水）片段与某些球状受体蛋白（核转运因子[NTFs]）上的疏水格罗夫斯丛短暂结合。 这些NTF可以同时结合指定流入或流出细胞核的货物分子。 在与NTF结合后，由于NTF与衬在孔中的核孔蛋白链之间的相互作用，货物被运送通过NPC孔。 Coalson小组试图使用粗粒度的计算机模型来澄清运输过程的关键细节，由于NPC的大小和规模，这些模型是合适的。 与此同时，NPC在体内的操作效率激发了合成聚合物涂层纳米孔的构建，这些纳米孔根据通过它们过滤的分子的大小和化学组成起分子筛的作用。 Coalson集团也将追求这些应用。 核孔复合体的缺陷会导致严重的疾病，包括癌症和许多传染病。NPC纳米孔与人类生理学的相关性表明，这项研究可能最终有助于改善人类健康，例如，通过开发药物来纠正它们的故障。在研究小组内，生物纳米孔研究与教学和推广活动协同进行，其中包括运行校内（匹兹堡大学）生物物理理论研讨会系列，以及创建和实施NSF资助的暑期研究所，专注于本科生和研究生的计算生物学。这些努力有助于生物纳米孔科学的教育，更普遍的是，分子生物物理学，在广泛的职业阶段和途径：从本科生到高级研究人员（自然科学家，工程师和医生）。此外，对合成纳米器件的研究，如聚合物涂层纳米孔，对纳米技术和纳米medicine.The Coalson组阐明纳米孔结构功能关系，通过开发新的物理化学接地粗粒度的模拟模型，结合创造性的统计力学分析，包括Flory-Huggins模型和自洽场理论近似。这些工具使研究更大的系统和更长的时间尺度比可以访问的全原子分子动力学模拟，即，介观尺度，其中许多大分子的集体行为影响孔隙选择分子货物通过它的能力。NPC结构和传输机制的细节激发了合成纳米图案的构建，其中将（非生物）聚合物分子接枝到圆柱形支架的内部，然后利用聚合物塌陷转变来打开和关闭这些纳米阀，从而使它们能够用于分析物分子的尺寸选择性筛选。 聚合物形态的变化可以通过特定纳米颗粒的渗透来控制，这些纳米颗粒以适当的量被引入溶液中。 同样，Coalson小组设计了聚合物涂层纳米球（例如，球形胶体颗粒）优先粘附到相关流动空间内的特定表面（例如，生物细胞）。 该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

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 infectiousdiseases. 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.