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

在化学系大分子、超分子和纳米化学项目的支持下，布拉德利L。罗切斯特大学的Nilsson、新泽西理工学院的Cristiano Dias和弗吉尼亚大学的Edward Egelman将研究肽的超分子自组装成纳米纤维生物材料。肽是在所有生物体中发现的天然存在的分子，其执行重要的生物学功能，包括充当信号激素，包括诸如胰岛素和催产素的生物活性肽。肽可以采用不同的构象，从而影响它们相互作用的方式。β折叠是一种常见的肽结构基序。呈现β-折叠构象的肽通常快速自组装成纳米原纤维。这些纳米原纤维组件中的一些与蛋白质错误折叠疾病如阿尔茨海默氏病有关，而另一些则被设计成功能性生物材料。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。新的β-片层材料，“波纹”β-片层，这是从自然界中发现的“褶皱”β-片层不同，将使用实验和计算技术进行研究。这些努力将为天然和人工β-折叠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基于肽的纳米材料的设计开辟新的途径。与这项工作有关的外联活动包括一门关于水凝胶的微型探究课程，名为“黏泥科学”，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接触。根据这一奖项的合作罗切斯特，NJIT，弗吉尼亚州的研究小组将通过确定这些系统的结构来研究由镜像肽组成的β-折叠纳米纤维的超分子组装，这些系统具有近-原子精度，并通过使用计算机模拟来研究驱动这些组件形成的力。这项工作是针对波纹β-折叠纳米原纤系统的合理设计。在第一个目标中，冷冻电子显微镜将被用来阐明相关的褶皱和波纹β-片层组件的结构和互补的计算分析将被用来合理化其组装机制。 在第二个目标中，将使用计算方法来预测和设计新的自组装β-折叠肽材料，并对这些预测进行实验测试。实验结果将用于验证和改进预测计算。这项工作的目的是提供有关肽自组装过程的分子基础的关键知识，这将是相关的理解蛋白质错误折叠过程和生物材料的设计与能源科学和生物医学的潜在应用。这个奖项反映了NSF的法定使命，并已被认为是值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估的支持。

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.