Sophistication of beta-Peptide Bundle Form and Function

在国家科学基金会化学系有机动力学项目和分子和细胞生物科学系生物分子系统项目的支持下，耶鲁大学化学系的Alanna Schepartz教授将尝试更好地了解生物聚合物中的非共价键。Schepartz教授报告了第一个非蛋白质类四元折叠的例子，这种折叠在结构上是独特的，在物理上也有很好的特征。这种“Foldein”由8个拷贝的12聚体β-多肽Zwit-1F组成，螺旋束排列，其动力学和热力学性质与天然蛋白质几乎没有区别。该提案中的实验建立在这一发现的基础上，以探索β-肽束稳定性的起源和决定因素，并评估这种结构在了解蛋白质折叠和开发复杂材料和催化剂方面的潜力。人们的期望是，从这项工作中获得的洞察力将使β-肽折叠蛋白充分发挥其作为生物学、纳米工程和医学工具的潜力。同时，识别多肽高阶组装的规则将加深对天然蛋白质折叠的理解。最后，复杂的和功能性的β-折叠蛋白的发展促使人们质疑α-氨基酸蛋白质的进化适合性，并推测为什么20种常见的氨基酸成为生命的基石。谢巴茨教授将为研究生、本科生和高中生提供宝贵的教学和学习机会，同时促进最高水平的发现。由于这项建议中描述的研究是跨学科的，参与其中的学生将掌握一组独特的和非常受欢迎的学科：有机合成、肽化学、生物有机化学/化学生物学和生物物理学。这种技能和知识广度的结合将确保这些学生继续为国家和国际科学事业做出持久而有价值的贡献。此外，值得注意的是，本提案中概述的一小部分实验是在教育阶梯的多个层面上进行协作的。此外，实验的一个子集将包括在二年级化学生物学实验室，这是一门由舍帕茨教授为耶鲁大学学生设计的课程。最后，Schepartz教授仍然坚定地致力于多样性的原则和实践，自1988年以来一直保持着一个由许多女性(50%)和代表不足的少数族裔学生组成的研究小组。

With the support of the Organic Dynamics Program in the Chemistry Division and the Biomolecular Systems Program in the Division of Molecular and Cellular Biosciences both at the National Science Foundation, Professor Alanna Schepartz of the Chemistry Department at Yale University will attempt to better understand the non-covalent bond in biopolymers. Professor Schepartz reported the first example of a non-proteinaceous quaternary fold that is both structurally unique and physically well characterized. This "foldein" consists of eight copies of the 12-mer beta-peptide Zwit-1F arranged in a helical bundle whose kinetic and thermodynamic properties are virtually indistinguishable from natural proteins. The experiments in the proposal build on that discovery to explore the origins and determinants of beta-peptide bundle stability and assess the potential of this structure to inform understanding of protein folding and develop sophisticated materials and catalysts. The expectation is that the insight gained from the work will allow beta-peptide foldeins to realize their full potential as tools in biology, nanoscale engineering, and medicine. At the same time, identification of rules governing â-peptide higher order assembly will deepen understanding of folding in natural proteins. Finally, the development of complex and functional beta-foldeins prompts one to question the evolutionary fitness of alpha-amino acid proteins and speculate why the 20 common amino acids have become the building blocks of life. Professor Schepartz will provide valuable teaching and learning opportunities to graduate students, undergraduates, and high school students, while simultaneously advancing discovery at the very highest level. As the research described in this proposal is interdisciplinary, the students involved will master a unique and highly desirable set of disciplines: organic synthesis, peptide chemistry, bioorganic chemistry/chemical biology, and biophysics. This combination of skills and breadth of knowledge will ensure that these students continue to make lasting and valuable contributions to the national and international scientific enterprise. It is noted that in addition that a fraction of the experiments outlined in this proposal are collaborative at multiple levels of the educational ladder. In addition, a subset of the experiments will be included in Chemical Biology for Sophomores Laboratory, a course designed by Professor Schepartz for Yale College students. Finally, Professor Schepartz remains deeply committed to the principles and practices of diversity, having maintained since 1988 a research group with numerous women ( 50%) and underrepresented minority students.