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

肽和合成折叠体螺旋的构象异构体特异性光谱和异构化动力学

• 批准号: 1764148
• 负责人: Scott McLuckey
• 金额: $ 48万
• 依托单位: Purdue University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2022-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1764148&HistoricalAwards=false
• 关键词: Conformer; specific; Spectroscopy; Isomerization; Dynamics

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.

大多数生物相关分子（例如，蛋白质和DNA）都足够大，它们可以呈现许多分子形状，这是由内部（“分子内”）相互作用以及与周围溶剂或其他邻近分子相互作用的微妙平衡所决定的。天然存在的多肽和蛋白质的一种常见折叠模式（称为“折叠体”）是α -螺旋，由蛋白质氨基酸成分之间的氢键（“h键”）连接在一起。然而，合成化学家正在设计新的氨基酸构建模块，它们更倾向于其他氢键排列（称为“合成折叠体”），包括具有多种不同氢键模式的螺旋结构。在这个由化学部门化学结构动力学和机理（CSDM-A）项目资助的项目中，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以新的方式探测这些螺旋及其相互转换。他们将这些分子从自然环境中取出，通过激光解吸或电喷雾电离将其带入气相，并将其冷却到绝对零度以下几度的温度。在这样做的过程中，他们在没有溶剂作用和不受样品中可能存在的其他构象干扰的情况下探测每个分子构象的独特性质。然后，激光光谱工具探测每个螺旋中的氢键网络，并揭示为什么一些折叠体比其他折叠体更受青睐，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。这个研究项目通过对试图预测分子形状和运动的理论模型提供深刻的实验测试，对整个社会产生了影响。参与该项目的研究生和本科生正在接受高技术产业、学术界和政府实验室的职业培训。茨维尔研究小组继续与主要的本科院校（PUI）合作，即教授。UW-Eau Claire的Stephen Drucker和Fairfield大学的Matt Kubasik)，从而加强了对更广泛的本科生的培训，并为研究生提供了独特的职业准备机会。Zwier团队正在采用一系列基于激光的光谱方法，在红外（IR）和紫外（UV）光谱区域获得气相肽的单构象光谱。激光解吸和电喷雾电离用于使分子或离子进入气相。通过超音速膨胀或低温冷却使样品温度低于10K。然后使用UV光破碎和UV- ir双共振技术对气相物种进行询问。特别感兴趣的是固有的构象偏好和独特的振动和电子吸收的天然和合成折叠体螺旋。其中一些分子结合了分子“系绳”，将螺旋“锁”在适当的位置。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。获得的实验光谱为螺旋相互转换的机制和能量需求提供了新的见解，并为最先进的计算（从头算、密度泛函理论和在无溶剂的情况下对分子进行的半经验力场计算）的准确性提供了基准测试。除了对理论模型进行基准测试和对学生进行培训外，这项研究的发现还促进了我们对合成文件夹的理解，这些文件夹可能在新材料和疾病治疗中有应用。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

项目成果

Single-Conformation Spectroscopy of Capped Aminoisobutyric Acid Dipeptides: The Effect of C-Terminal Cap Chromophores on Conformation

加帽氨基异丁酸二肽的单构象光谱：C 端帽发色团对构象的影响

• DOI: 10.1021/acs.jpca.9b01698
• 发表时间: 2019
• 期刊: The Journal of Physical Chemistry A
• 作者: Fischer, Joshua L.;Elvir, Brayan R.;DeLucia, Sally-Ann;Blodgett, Karl N.;Zeller, Matthias;Kubasik, Matthew A.;Zwier, Timothy S.
• 通讯作者: Zwier, Timothy S.

Single-conformation spectroscopy of cold, protonated D PG-containing peptides: switching β-turn types and formation of a sequential type II/II′ double β-turn

含冷质子化 D PG 肽的单构象光谱：切换 β 转角类型并形成连续的 II/II 型双 β 转角

• DOI: 10.1039/d1cp04852j
• 发表时间: 2022
• 期刊: Physical Chemistry Chemical Physics
• 影响因子: 3.3
• 作者: Lawler, John T.;Harrilal, Christopher P.;DeBlase, Andrew F.;Sibert, Edwin L.;McLuckey, Scott A.;Zwier, Timothy S.
• 通讯作者: Zwier, Timothy S.

Vibronic spectroscopy of methyl anthranilate and its water complex: hydrogen atom dislocation in the excited state

• DOI: 10.1039/c9cp04556b
• 发表时间: 2019-10-14
• 期刊: PHYSICAL CHEMISTRY CHEMICAL PHYSICS
• 影响因子: 3.3
• 作者: Blodgett, Karl N.;Sun, Dewei;Zwier, Timothy S.
• 通讯作者: Zwier, Timothy S.

Conformation-Specific Spectroscopy of Asparagine-Containing Peptides: Influence of Single and Adjacent Asn Residues on Inherent Conformational Preferences

• DOI: 10.1021/acs.jpca.8b08418
• 发表时间: 2018-11-08
• 期刊: JOURNAL OF PHYSICAL CHEMISTRY A
• 影响因子: 2.9
• 作者: Blodgett, Karl N.;Fischer, Joshua L.;Zwier, Timothy S.
• 通讯作者: Zwier, Timothy S.

Coexistence of Left- and Right-Handed 12/10-Mixed Helices in Cyclically Constrained β-Peptides and Directed Formation of Single-Handed Helices upon Site-Specific Methylation

循环约束 β 肽中左手和右手 12/10 混合螺旋的共存以及位点特异性甲基化时单手螺旋的定向形成

• DOI: 10.1021/acs.jpca.0c03545
• 发表时间: 2020
• 期刊: The Journal of Physical Chemistry A
• 作者: Blodgett, Karl N.;Jang, Geunhyuk;Kim, Sojung;Kim, Min Kyung;Choi, Soo Hyuk;Zwier, Timothy S.
• 通讯作者: Zwier, Timothy S.