From the Nuclear Pore Complex to Smart Artificial Nanochannels

从核孔复合体到智能人工纳米通道

• 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

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.

人类细胞将DNA存储在细胞核内。核孔复合物是核包膜上的大蛋白质复合物，其作用像核进口和出口的检查点。每个核孔复合物仅选择所有蛋白质类型的0.1％，并以每秒约1000个分子的速率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来控制许多不同的生物分子的运输仍然是一个谜。理解这种自然界建造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，这些纳米孔将有助于解决许多现实世界中的物质问题，例如水的脱盐和能量转换。核孔复合物中的守门人是生物聚合物（面条样分子），其结构是高度动态的，很难被实验捕获。在这项拟议的工作中，PI将采用理论方法来揭示核孔结构的奥秘。建模工作将集中于门控蛋白的功能结构。基于对核孔复合物的更好理解，PI将设计由合成聚合物功能化的智能人工纳米孔，以实现有效的分子滤波和对环境的敏感反应。设计的纳米孔将由实验合作者在项目上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的主要特征是亲水性（水状）和疏水（油状）氨基酸在序列上的交替布置，在它们的序列上，派发了复杂的液体纳米环境，以支持多个液体nano-Enmentment，以支持多个核能。激烈争议的是两亲性苯丙氨酸 - 甘氨酸-NUP是否假定凝胶状或刷状结构。为了解决这个问题，PI开发了一种分子理论，该理论明确说明了分子构象，静电，疏水相互作用，排除体积效应和酸碱平衡，并在适当的粗粒粒度水平上。 PI的先前工作表明，静电和疏水相互作用耦合在核孔内，从而导致对核转运的不添加作用。在该研究项目中，PI将进一步绘制不同疏水官能团的空间分布，这将允许鉴定各种核运输途径。通过改善PI的理论显微镜分辨率，可以测试核结构的不同假设。使用PI开发的模型，可以轻松地更改聚合物序列相互作用强度和移植位置，以研究其对门控性能的影响。此类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反应的组合，以设计具有多个功能的纳米孔。另一方面，为了利用用于人造纳米版的固态材料，PI将研究表面对移植/吸附聚合物自组装的曲率效应。通过整合刺激反应，序列设计和曲率控制，将展示下一代纳米孔和超越生物学的潜力。该奖项反映了NSF的法定任务，并被认为是值得通过基金会的知识分子优点和更广泛影响的审查标准来通过评估来支持的。

项目成果

Influence of Membrane Permittivity on Charge Regulation of Weak Polyelectrolytes End-Tethered in Nanopores

• DOI: 10.1021/acs.macromol.2c01391
• 发表时间: 2022-09
• 期刊: Macromolecules
• 影响因子: 5.5
• 作者: Shiyi Qin;Rikkert J. Nap;Kai Huang;I. Szleifer

Voltage-Triggered Structural Switching of Polyelectrolyte-Modified Nanochannels

• DOI: 10.1021/acs.macromol.0c00082
• 发表时间: 2020-04-14
• 期刊: MACROMOLECULES
• 影响因子: 5.5
• 作者: Perez Sirkin, Yamila A.;Szleifer, Igal;Tagliazucchi, Mario
• 通讯作者: Tagliazucchi, Mario

Design of Multifunctional Nanopore Using Polyampholyte Brush with Composition Gradient

• DOI: 10.1021/acsnano.1c05543
• 发表时间: 2021-11-23
• 期刊: ACS NANO
• 影响因子: 17.1
• 作者: Qin, Shiyi;Huang, Kai;Szleifer, Igal
• 通讯作者: Szleifer, Igal

Nanocompartmentalization of the Nuclear Pore Lumen

• DOI: 10.1016/j.bpj.2019.11.024
• 发表时间: 2020-01-07
• 期刊: BIOPHYSICAL JOURNAL
• 影响因子: 3.4
• 作者: Huang, Kai;Tagliazucchi, Mario;Szleifer, Igal
• 通讯作者: Szleifer, Igal

Structure and dynamics of nanoconfined water and aqueous solutions

• DOI: 10.1140/epje/s10189-021-00136-4
• 发表时间: 2021-11-01
• 期刊: EUROPEAN PHYSICAL JOURNAL E
• 影响因子: 1.8
• 作者: Corti, Horacio R.;Appignanesi, Gustavo A.;Szleifer, Igal
• 通讯作者: Szleifer, Igal