Collaborative Research: Supramolecular Multi-Component Peptide Nanofibrils: Bridging Understanding at Atomic and Mesoscopic Scales with Structure and Theory

合作研究：超分子多组分肽纳米纤维：通过结构和理论在原子和介观尺度上架起理解桥梁

• 批准号: 2304852
• 负责人: Bradley Nilsson
• 金额: $ 40万
• 依托单位: University of Rochester
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2304852&HistoricalAwards=false
• 关键词: Collaborative; Research; Supramolecular; Multi; Component

With the support of the Macromolecular, Supramolecular and Nanochemistry Program in the Division of Chemistry, Bradley L. Nilsson of the University of Rochester, Cristiano Dias of the New Jersey Institute of Technology (NJIT), and Edward Egelman of the University of Virginia will study the supramolecular self-assembly of peptides into nanofibril biomaterials. Peptides are naturally occurring molecules found in all organisms that perform important biological functions, including acting as signaling hormones, including such bioactive peptides as insulin and oxytocin. Peptides can adopt different conformations that influence how they interact with each other. Beta-sheets are one common peptide structural motif. Peptides that assume beta-sheet conformations often rapidly self-assemble into nanofibrils. Some of these nanofibril assemblies are associated with protein misfolding disorders like Alzheimer’s disease and others have been designed to be functional biomaterials. In this work, the team will study how these peptides the co-assemble into these structures. Novel beta-sheet materials, “rippled” beta-sheets, that are distinct from the “pleated” beta-sheets found in nature, will be studied using experimental and computational techniques. These efforts will provide critical insight into the structure of both natural and artificial beta-sheets and the molecular-scale interactions that dictate the assembly of these materials. This research is directed at opening up new avenues for the design of next generation peptide-based nanomaterials. Outreach activity associated with this work includes an inquiry based mini-course on hydrogels called “The Science of Slime” which will be conducted at the participating institutions for pre-university students from grades 7-12. Additionally, the research teams will host high school interns for six weeks during the summer to provide mentoring and increase exposure to scientific research and to the chemical sciences, in general.Under this award the collaborative Rochester, NJIT, Virginia team will investigate the supramolecular assembly of beta-sheet nanofibrils composed of mirror-image peptides by determining the structure of these systems with near-atomic precision and by using computer simulations to investigate the forces driving the formation of these assemblies. This work is directed at the rational design of rippled beta-sheet nanofibril systems. In the first objective, cryo-electron microscopy will be used to elucidate the structure of related pleated and rippled beta-sheet assemblies and complementary computational analyses will be used to rationalize their mechanisms of assembly. In the second objective, computational methods will be used to predict and design novel self-assembled beta-sheet peptide materials and these predictions will be tested experimentally. The results of the experiments will be used to validate and improve predictive computations. This work aims to provide key knowledge regarding the molecular basis for peptide self-assembly processes that will be relevant to understanding protein misfolding processes and for the design of biomaterials with potential applications in energy science and biomedicine.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.

在化学系大分子、超分子和纳米化学项目的支持下，罗切斯特大学的Bradley L. Nilsson、新泽西理工学院（NJIT）的Cristiano Dias和弗吉尼亚大学的Edward Egelman将研究多肽的超分子自组装成纳米纤维生物材料。肽是一种天然存在的分子，存在于所有生物体中，具有重要的生物功能，包括作为信号激素，包括胰岛素和催产素等生物活性肽。多肽可以采用不同的构象来影响它们相互作用的方式。-片是一种常见的肽结构基序。具有-薄片构象的多肽通常会迅速自组装成纳米原纤维。其中一些纳米纤维组装与蛋白质错误折叠障碍（如阿尔茨海默病）有关，而另一些则被设计为功能性生物材料。在这项工作中，研究小组将研究这些肽如何共同组装成这些结构。新型的β -薄片材料，“波纹”β -薄片，不同于自然界中发现的“褶皱”β -薄片，将使用实验和计算技术进行研究。这些努力将为了解天然和人工β -片的结构以及决定这些材料组装的分子尺度相互作用提供关键的见解。这项研究旨在为下一代肽基纳米材料的设计开辟新的途径。与这项工作相关的外展活动包括一门名为“黏液科学”的基于探究的水凝胶迷你课程，该课程将在参与机构为7-12年级的大学预科学生开设。此外，研究团队将在夏季接待高中实习生六周，以提供指导，并增加对科学研究和化学科学的了解。根据该合同，该团队将研究由镜像肽组成的-薄片纳米纤维的超分子组装，方法是以接近原子的精度确定这些系统的结构，并使用计算机模拟来研究驱动这些组装形成的力。这项工作是针对波纹纳米纤维系统的合理设计。在第一个目标中，冷冻电子显微镜将用于阐明相关的褶状和波纹状β -薄片组装的结构，并使用补充的计算分析来合理化它们的组装机制。在第二个目标中，计算方法将用于预测和设计新的自组装β -片肽材料，这些预测将在实验中进行测试。实验结果将用于验证和改进预测计算。这项工作旨在提供关于肽自组装过程的分子基础的关键知识，这将与理解蛋白质错误折叠过程和设计具有潜在应用于能源科学和生物医学的生物材料有关。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。