From the Nuclear Pore Complex to Smart Artificial Nanochannels

人类细胞将DNA储存在细胞核内。核孔复合物是位于核包膜上的大型蛋白质复合物，起着核进出口的检查点作用。每个核孔复合体只选择所有蛋白质类型的0.1%，并以每秒约1000分子的速度通过核包膜运输它们。核孔复合物如何以如此高的效率和选择性控制如此多的不同生物分子的运输仍然是一个谜。了解这种由自然形成的最复杂的生物纳米孔有望激发下一代人造纳米孔的设计，这将有助于解决许多现实世界的材料问题，如海水淡化和能量转换。核孔复合体内部的守门人是生物聚合物（面条状分子），其结构是高度动态的，难以通过实验捕获。在这项拟议的工作中，PI将使用理论方法来解开核孔结构的奥秘。建模工作将集中在门控蛋白的功能结构上。在更好地了解核孔复合物的基础上，PI将设计由合成聚合物功能化的智能人工纳米孔，以实现高效的分子过滤和对环境的敏感响应。设计的纳米孔将由项目的实验合作者进行计算优化和测试。本科生和研究生由PI进行培训。F（苯丙氨酸）-G（甘氨酸）-Nups的一个主要特征是亲水性（类水）和疏水性（类油）氨基酸在其序列上的交替排列，形成了一个复杂的液体纳米环境，支持核运输的多种途径。对于两亲性苯丙氨酸-甘氨酸-氨基酸是凝胶状结构还是刷子状结构一直存在激烈的争论。为了解决这个问题，PI开发了一种分子理论，可以在适当的粗粒度水平上明确地解释分子构象、静电、疏水相互作用、排除体积效应和酸碱平衡。PI先前的工作表明，静电和疏水相互作用在核孔内耦合，导致核传输的非加性效应。在这个研究项目中，PI将进一步绘制不同疏水官能团的空间分布，这将允许识别各种核运输途径。通过提高PI的分辨率？通过理论显微镜，可以检验不同的核结构假设。利用PI建立的模型，可以很容易地改变聚合物序列、相互作用强度和接枝位置，从而研究它们对浇注性能的影响。该系统研究的见解将阐明基于聚合物的合成纳米孔的设计原则。PI将探索合成功能基元与不同刺激反应的结合，以设计具有多种功能的纳米孔。另一方面，为了利用固态材料制造人造纳米器件，PI将研究表面曲率对接枝/吸附聚合物自组装的影响。通过整合刺激反应、序列设计和曲率控制，下一代纳米孔的潜力将被展示出来。该奖项反映了美国国家科学基金会的法定使命，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。

Human cell stores DNA inside the nucleus. Nuclear pore complexes are large protein complexes on the nuclear envelope, acting like checkpoints for the nuclear import and export. Each nuclear pore complex selects only 0.1 percent of all the protein types and transports them through the nuclear envelope at a rate of around 1000 molecules per second. It is still a mystery how the nuclear pore complex controls the transport of so many different biomolecules with such a high efficiency and selectivity. Understanding this most sophisticated biological nanopore built by nature is expected to inspire the design of next-generation man-made nanopores that will help solve many real-world material problems such as water desalination and energy conversion. The gatekeepers inside the nuclear pore complex are biological polymers (noodle-like molecules) whose structures are highly dynamic and hard to be captured by experiments. In this proposed work the PI will use a theoretical approach to unravel the mystery of the nuclear pore structure. The modeling effort will focus on the functional structure of the gating proteins. Based on a better understanding of the nuclear pore complex, the PI will design smart artificial nanopores functionalized by synthetic polymers to achieve efficient molecular filtering and sensitive response to the environment. The designed nanopores will be computationally optimized and tested by the experimental collaborators on the project. Undergraduate and graduate students will be trained by the PI.One primary feature of the F(phenylalanine)-G(glycine)-Nups is the alternating arrangement of hydrophilic (water-like) and hydrophobic (oil-like) amino acids on their sequences, rendering a complex liquid nano-environment that supports multiple pathways for nuclear transport. It has been heatedly debated whether the amphiphilic phenylalanine-glycine-Nups assume a gel-like or brush-like structure. To address this question, the PI has developed a molecular theory that explicitly accounts for the molecular conformations, electrostatics, hydrophobic interactions, excluded volume effects and acid-base equilibrium at a properly coarse-grained level. Previous work by the PI revealed that the electrostatic and hydrophobic interactions are coupled inside the nuclear pore, leading to a non-additive effect on the nuclear transport. In this research project, the PI will further map the spatial distributions of different hydrophobic functional groups, which will allow for the identification of various nuclear transport pathways. By improving the resolution of the PI?s theoretical microscope, different hypotheses of the nuclear structure can be tested. Using the model developed by the PI, the polymer sequence interaction strength and grafting position can be easily changed to study their effects on the gating performance. The insights from such systematic study will elucidate the design principles for polymer-based synthetic nanopores. The PI will explore the combination of synthetic functional motifs with different stimuli-responses to design nanopores with multiple functions. On the other hand, to take advantage of solid-state materials for artificial nanodevices, the PI will investigate the curvature effect of surface on the self-assembly of grafted/adsorbed polymers. By integrating stimuli-response, sequence-design and curvature-control, the potential of next-generation nanopores inspired and beyond biology will be demonstrated.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.