Single Conformation Spectroscopy and Isomerization Dynamics of Synthetic Foldamers

在这项由化学系实验物理化学项目资助的奖项中，普渡大学的Timothy Zwier教授和他的研究生和本科生将研究一系列含有2-10个残基的β-肽、伽马肽和杂化(例如，α/β)合成叶酰胺的光谱和异构化动力学。这些分子将被研究为在超音速膨胀中冷却的孤立中性分子，或者作为在低温冷却离子陷阱中冷却到10K的离子。重点将放在与自然产生的阿尔法肽不同的分子上，这些分子的酰胺基团之间有一个(贝塔)或两个(伽马)额外的碳原子，使它们具有额外的灵活性，并开辟了更广泛的二级结构，要么模仿自然中发现的二级结构，要么改进这些二级结构。Zwier教授和他的团队将使用基于激光的方法，使他们能够在不受彼此干扰的情况下记录单一构象的红外和紫外光谱，并确定它们的相对种群。这些结果还将为蛋白质和合成折叠剂行为的计算机模型的准确性提供基准测试。最后，激光将被用来引发构象异构化，以确定与异构化过程相关的能量、时间尺度和能量流。这项研究项目将通过提供对这些合成叶酰胺内在结构偏好的基本见解来影响整个社会，合成化学家正将其应用于广泛的生物医学和药物发现应用。威斯康星大学麦迪逊分校的萨姆·盖尔曼和他的团队正在合作进行这项研究，他们合成了测试它们行为特定方面的折叠剂。为与特定生物受体相互作用而量身定做的独特螺旋支架的设计需要了解并控制构成它们的单个亚单位的结构偏好。与Foldamer领域领先的合成集团的强大合作确保了紧密耦合的反馈，这将使该项目的结果最大限度地受益于生物医学应用。

In this award, funded by the Experimental Physical Chemistry Program of the Division of Chemistry, Professor Timothy Zwier of Purdue University and his graduate and undergraduate students will investigate the spectroscopy and isomerization dynamics of a series of beta-peptide, gamma-peptide, and hybrid (e.g., alpha/beta) synthetic foldamers containing 2-10 residues. These molecules will be studied either as isolated neutral molecules cooled in a supersonic expansion or as ions cooled to 10 K in a cryo-cooled ion trap. The focus will be on molecules that differ from naturally-occurring alpha-peptides in having one (beta) or two (gamma) extra carbon atoms separating the amide groups, giving them additional flexibility and opening up a wider range of secondary structures that either mimic or improve on those found in nature. Professor Zwier and his team will use laser-based methods that enable them to record infrared and ultraviolet spectra of single conformations free from interference from one another, and to determine their relative populations. The results will also provide benchmark tests of the accuracy of computer models of the behavior of proteins and synthetic foldamers. Finally, lasers will be used to initiate conformational isomerization in order to determine the energies, time-scales, and energy flow associated with the isomerization process. This research project will impact society at large by providing fundamental insight to the inherent structural preferences of these synthetic foldamers, which are being applied by synthetic chemists to a wide range of biomedical and drug-discovery applications. Sam Gellman and his group at University of Wisconsin-Madison are collaborating in this study, synthesizing foldamers that test particular aspects of their behavior. The design of unique helical scaffolds tailor-made to interact with specific biological receptors requires a knowledge of, and control over, the structural preferences of the individual sub-units of which they are made. The strong collaboration with a leading synthetic group in the foldamer field ensures close-coupled feedback that will maximize the benefit of this project's results towards biomedical applications.