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: 2304854
• 负责人: Edward Egelman
• 金额: $ 20万
• 依托单位: University of Virginia Main Campus
• 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=2304854&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.

在化学系高分子、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将进行研究肽通过超分子自组装形成纳米原纤维生物材料 肽是所有生物体中天然存在的分子，具有重要的生物功能，包括充当信号传导功能。肽，包括胰岛素和催产素等生物活性肽，可以采用不同的构象，从而影响它们之间的相互作用。β-折叠结构是一种常见的肽结构基序，通常会快速自组装成纳米原纤维。其中一些纳米原纤维组件与阿尔茨海默氏病等蛋白质错误折叠疾病有关，而其他纳米原纤维组件则被设计为功能性生物材料。将使用实验和计算技术来研究新型β-折叠材料，即“波纹”β-折叠，它与自然界中发现的“褶皱”β-折叠不同。这项研究旨在为下一代基于肽的纳米材料的设计开辟新的途径。和这项工作包括一门基于探究的水凝胶迷你课程，名为“粘液科学”，该课程将在参与机构为 7 至 12 年级的大学预科学生开设。此外，研究团队还将接待高中实习生为期六周。夏季提供指导并增加对科学研究和化学科学的接触。根据该奖项，弗吉尼亚州新泽西理工学院罗切斯特分校的合作团队将研究由镜像组成的 β-片层纳米纤维的超分子组装这项工作的第一个目标是通过以接近原子的精度确定这些系统的结构并研究驱动这些组件形成的力。冷冻电子显微镜将用于阐明相关的褶皱和波纹β-折叠组件的结构，并且将使用补充计算分析来合理化其组装机制。在第二个目标中，计算方法将用于合理化其组装机制。用于预测和设计新型自组装β-折叠肽材料，这些预测将通过实验进行测试，实验结果将用于验证和改进预测计算。这项工作旨在提供有关分子基础的关键知识。肽自组装过程将与理解蛋白质错误折叠过程以及设计具有能源科学和生物医学潜在应用的生物材料相关。该奖项反映了 NSF 的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准。