Conformer-specific Spectroscopy and Isomerization Dynamics of Peptide and Synthetic Foldamer Helices

大多数生物学相关分子（例如蛋白质和DNA）都足够大，以至于它们可以呈现出许多分子形状，这取决于内部（“分子内”）相互作用和与周围溶剂或其他相邻分子相互作用的微妙平衡。天然存在的肽和蛋白质的常见折叠模式（称为“折叠体”）之一是α-螺旋，其通过蛋白质的氨基酸组分之间的氢键（“H-键”）保持在一起。然而，合成化学家正在设计新的氨基酸构建块，它们更喜欢其他氢键排列（称为“合成折叠体”），包括具有各种不同氢键模式的螺旋。在这个由化学部化学结构动力学和机制（CSDM-A）计划资助的项目中，普渡大学的Timothy Zwier教授正在使用一系列基于激光的光谱方法来探测这些螺旋及其相互转换。他们通过激光解吸或电喷雾电离将这些分子带入气相，将它们从自然环境中取出，并将其冷却到绝对零度几度以内。在这样做的过程中，他们在没有溶剂效应的情况下探测每个分子构象的独特性质，并且不会受到样品中可能存在的其他构象的干扰。然后，激光光谱工具探测每个螺旋中的氢键网络，并揭示为什么某些折叠体比其他折叠体更受欢迎，以及从一种折叠体形式转变为另一种折叠体形式需要多少能量。该研究项目通过对试图预测分子形状和运动的理论模型进行深入的实验测试，对整个社会产生影响。参与该项目的研究生和本科生正在接受高科技行业，学术界和政府实验室的职业培训。Zwier研究小组继续与主要的本科院校（PUI，即教授）合作。Zwier的团队正在使用一系列基于激光的光谱学方法来获得气相肽在红外（IR）和紫外（UV）光谱区域的单一构象光谱。 激光解吸和电喷雾电离用于将分子或离子带入气相。通过超声膨胀或低温冷却使样品温度低于10 K。 气相物种，然后询问使用UV光裂解和UV-IR双共振技术。特别令人感兴趣的是天然和合成折叠体螺旋的固有构象偏好和独特的振动和电子选择。这些分子中的一些结合了分子“系绳”，该分子“锁定”螺旋的位置。另一方面，合成到分子骨架中的构象约束可能导致分子以特定的方式折叠。获得的实验光谱是借贷新的见解螺旋相互转换的机制和能量要求，并提供基准测试的准确性国家的最先进的计算（从头算，密度泛函理论和半经验力场计算分子在溶剂的情况下）。 除了理论模型的基准和学生的培训，这项研究的结果正在推进我们对合成折叠分子的理解，这可能在新材料和疾病治疗中有应用。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进行评估，被认为值得支持。

Most biologically relevant molecules (for example, proteins and DNA) are large enough that they can take on many molecular shapes, dictated by a delicate balance of internal ("intramolecular") interactions and interactions with the surrounding solvent or other neighboring molecules. One of the common folding patterns (called "foldamers") of naturally occurring peptides and proteins are alpha-helices, held together by hydrogen bonds ("H-bonds") between the amino acid constituents of the protein. However, synthetic chemists are designing new amino acid building blocks that prefer other hydrogen bonding arrangements (called "synthetic foldamers"), including helices with a wide array of different hydrogen bonding patterns. In this project funded by the Chemical Structure Dynamics and Mechanism (CSDM-A) program of the Chemistry Division, Professor Timothy Zwier of Purdue University is using an array of laser-based spectroscopy methods to probe these helices and their interconversions in new ways. They take these molecules out of their natural environment by bringing them into the gas phase via laser desorption or electrospray ionization, and cool them to temperatures within a few degrees of absolute zero. In so doing, they probe the unique properties of each molecular conformation in the absence of solvent effects and without interference from the other conformations that may be present in the sample. Laser spectroscopic tools then probe the network of H-bonds in each helix, and reveal why some foldamers are preferred over others, and how much energy is needed to change from one foldamer form to another. This research project impacts society at large by providing incisive experimental tests of theoretical models that attempt to predict the shape and motions of molecules. Graduate and undergraduate students involved in the project are being trained for careers in high-technology industry, academia, and government laboratories. The Zwier research group continues to collaborate with predominantly undergraduate institutions (PUI, namely Profs. Stephen Drucker of UW-Eau Claire and Matt Kubasik at Fairfield University), thus enhancing the training of a broader range of undergraduate students, and provide unique career preparation opportunities for graduate students.The Zwier group is employing an array of laser-based spectroscopic methods for obtaining single-conformation spectra of gas-phase peptides in the infrared (IR) and ultraviolet (UV) spectral regions. Laser desorption and electrospray ionization are used to bring molecules or ions into the gas phase. Samples temperatures are brought below 10K via supersonic expansion or cryo-cooling. The gas-phase species are then interrogated using UV photo-fragmentation and UV-IR double-resonance techniques. Of particular interest are the inherent conformational preferences and unique vibrational and electronic absorptions of of natural and synthetic foldamer helices. Some of these molecules incorporate a molecular "tether" that "locks" the helix in place. On the other hand, conformational constraints synthesized into the molecular backbone may cause the molecule to fold in a specific way. The experimental spectra obtained are lending new insights into the mechanism and energy requirements for helix interconversion, and provide benchmark tests of the accuracy of state-of-the-art calculations (ab initio, density functional theory and semi-empirical force field calculations done on molecules in the absence of solvent). In addition to the benchmarking of theoretical models and the training of students, the findings of this research are advancing our understanding of synthetic foldamers, which may have applications in new materials and the treatment of disease.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.