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、超分子和纳米化学计划的支持下，罗切斯特大学的布拉德利·L·尼尔森、新泽西理工学院(NJIT)的克里斯蒂亚诺·迪亚斯和弗吉尼亚大学的爱德华·埃格尔曼将研究多肽的超分子自组装成纳米纤维生物材料。多肽是在所有生物体中自然存在的分子，具有重要的生物学功能，包括作为信号激素，包括胰岛素和催产素等生物活性多肽。多肽可以采用不同的构象，从而影响它们相互作用的方式。β-折叠是一种常见的多肽结构基序。呈现β-折叠构象的多肽通常会迅速自组装成纳米纤维。其中一些纳米纤维组装与阿尔茨海默病等蛋白质错误折叠障碍有关，另一些则被设计成功能生物材料。在这项工作中，该团队将研究这些肽是如何共同组装成这些结构的。我们将使用实验和计算技术来研究不同于在自然界中发现的“折叠”的贝塔薄片的新型贝塔薄片材料--“波纹”贝塔薄片。这些努力将提供对天然和人工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的关键洞察力。本研究旨在为下一代基于多肽的纳米材料的设计开辟新的途径。与这项工作相关的外联活动包括将在参与机构为7-12年级的大学预科学生开设一门关于水凝胶的名为“黏液科学”的探究式迷你课程。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一般化学科学的接触。在这一奖项下，位于弗吉尼亚州新泽西州罗切斯特的合作团队将通过以近原子精度确定由镜像多肽组成的贝塔片状纳米纤维的结构，并通过使用计算机模拟来调查这些组装形成的驱动力，来研究这些组装的超分子组装。这项工作是针对波纹β-片状纳米纤维系统的合理设计。在第一个目标中，将使用冷冻电子显微镜来阐明相关的褶皱和波纹贝塔折叠组件的结构，并将使用互补的计算分析来合理地解释它们的组装机制。在第二个目标中，将使用计算方法来预测和设计新型的自组装β-片肽材料，并且这些预测将得到实验验证。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多肽自组装过程的分子基础的关键知识，这些知识将与理解蛋白质错误折叠过程以及设计在能源科学和生物医学中具有潜在应用的生物材料有关。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

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.