From the Nuclear Pore Complex to Smart Artificial Nanochannels

从核孔复合体到智能人工纳米通道

基本信息

批准号：
1833214
负责人：
Igal Szleifer
金额：
$ 33万
依托单位：
Northwestern University
依托单位国家：
美国
项目类别：
Standard Grant
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2022-08-31
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1833214&HistoricalAwards=false
关键词：
Nuclear Pore Complex Smart Artificial

项目摘要

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.

人体细胞将DNA储存在细胞核内。核孔复合物是核膜上的大型蛋白质复合物，充当核进出口的检查点。每个核孔复合体仅选择所有蛋白质类型的 0.1%，并以每秒约 1000 个分子的速度将它们运输通过核膜。核孔复合体如何以如此高的效率和选择性控制如此多不同的生物分子的运输仍然是一个谜。了解这种由大自然构建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，例如海水淡化和能源转换。核孔复合体内部的看门人是生物聚合物（面条状分子），其结构高度动态且难以通过实验捕获。在这项拟议的工作中，PI 将使用理论方法来揭开核孔结构的神秘面纱。建模工作将重点关注门控蛋白的功能结构。基于对核孔复合体的更好理解，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。设计的纳米孔将由该项目的实验合作者进行计算优化和测试。本科生和研究生将接受 PI 的培训。F（苯丙氨酸）-G（甘氨酸）-Nups 的一个主要特征是亲水性（类似水）和疏水性（类似油）氨基酸在其序列上交替排列，渲染复杂的液体纳米环境，支持多种核运输途径。两亲性苯丙氨酸-甘氨酸-Nups 是否呈现凝胶状或刷状结构一直存在激烈争论。为了解决这个问题，PI 开发了一种分子理论，该理论在适当的粗粒度水平上明确解释了分子构象、静电、疏水相互作用、排除体积效应和酸碱平衡。 PI之前的工作表明，静电和疏水相互作用在核孔内耦合，导致对核运输的非加和效应。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图，这将有助于识别各种核转运途径。通过提高 PI 理论显微镜的分辨率，可以测试核结构的不同假设。使用PI开发的模型，可以轻松改变聚合物序列相互作用强度和接枝位置，以研究它们对浇注性能的影响。这种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理。 PI将探索合成功能基序与不同刺激响应的结合，以设计具有多种功能的纳米孔。另一方面，为了利用固态材料用于人造纳米器件，PI将研究表面曲率对接枝/吸附聚合物自组装的影响。通过整合刺激响应、序列设计和曲率控制，将展示下一代纳米孔的激发和超越生物学的潜力。该奖项反映了 NSF 的法定使命，并通过使用基金会的智力优点和技术进行评估，被认为值得支持。更广泛的影响审查标准。