The Role of Thioamides in Natural and Designed Proteins

硫代酰胺在天然和设计蛋白质中的作用

• 批准号: 2203909
• 负责人: Ernest Petersson
• 金额: $ 51万
• 依托单位: University of Pennsylvania
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2203909&HistoricalAwards=false
• 关键词: Role; Thioamides; Natural; Designed; Proteins

With the support of the Chemistry of Life Sciences (CLP) program in the Division of Chemistry, Professor E. James Petersson from the University of Pennsylvania is studying the effects of thioamides, oxygen-to-sulfur substitutions of the peptide bond found in proteins. The results of these studies will further the development of thioamides as tools for biophysical and medicinal chemistry by providing rules for the rational design of thioamide proteins with or without affecting stability, as desired. The work will also help to explain the evolutionary value of the thioamides found in certain natural proteins. The planned investigations of the fundamental properties of thioamides can impact areas as diverse as epigenetics, the biophysics of protein folding, the design of enzyme inhibitors, or even fluorescence-guided surgery using thioamide-stabilized peptides as tumor imaging agents. The broader impacts of this work include training undergraduate and graduate students in a multidisciplinary laboratory environment that makes use of organic synthesis and physical chemistry, as well as molecular and cellular biology, to investigate biological phenomena. In addition, Professor Petersson and his research group will participate in expositions both in-person, and virtual, to demonstrate their findings to K-12 groups and interested adults. They will also help to build the Penn Chemistry Summer Research Academy so that more students from groups under-represented in science have opportunities to experience science and participate in scientific research.Under this project, the physical properties and reactivity of thioamides will be studied as a function of amino acid sequence in model peptides. This will aid in the mechanistic understanding of environment-dependent properties such as pKa, and in benchmarking quantum mechanical (QM) calculations. For example, there is a need to better develop in molecular mechanics parameters for tripeptides or polypeptides, rather than use parameters based on small molecule values as has been done heretofore. Reactivity studies will be performed that have the potential to develop tools to identify new natural thioamide-containing proteins. Professor Petersson’s laboratory will also study thioamide effects on the secondary and tertiary structure of peptides, peptide/protein host-guest systems, and full-length proteins. Using data from model systems, novel PyRosetta programs will be developed in an effort to predict the effects of thioamides on protein stability. These predictions will be tested on thioamide-containing proteins, which will be characterized through X-ray crystallography and/or NMR as well as solution-phase stability measurements. Taken together, these experiments are expected to provide a better systematic understanding of the effects of thioamides on protein properties from local sequence-based effects, to effects on secondary, tertiary, and even quaternary structure.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.

在化学生命科学（CLP）方案的支持下，宾夕法尼亚大学的E. James Petersson教授正在研究硫代酰胺，氧气对硫化物的替代肽的影响。这些研究的结果将进一步开发硫酰胺作为生物物理和医学化学的工具，通过根据需要根据或不影响稳定性的硫酰胺蛋白的合理设计规则。这项工作还将有助于解释某些天然蛋白质中发现的硫酰胺的进化价值。对硫酰胺的基本特性的计划研究可能会影响像表观遗传学，蛋白质折叠的生物物理学，酶抑制剂的设计，甚至使用硫酰胺稳定的Pepperides作为肿瘤成像剂。这项工作的更广泛影响包括在多学科实验室环境中培训本科生和研究生，该实验室环境利用有机合成和物理化学以及分子和细胞生物学来研究生物学现象。此外，彼得森教授及其研究小组将参加面对面的博览会和虚拟的博览会，向K-12组和感兴趣的成年人展示他们的发现。他们还将有助于建立宾夕法尼亚化学夏季研究学院，以便从科学领域代表不足的群体的更多学生有机会体验科学并参与科学研究。在该项目下，将研究硫酰胺的物理性能和反应性，作为模型肽中氨基酸序列的函数。这将有助于对环境依赖性特性（例如PKA）的机械理解，并在基准测试量子机械（QM）计算中。例如，需要更好地发展三肽或多肽的分子力学参数，而不是像迄今为止所做的那样基于小分子值的参数。将进行反应性研究，该研究有可能开发工具以鉴定新的含硫酰胺的蛋白质。彼得森教授的实验室还将研究硫酰胺对肽，胡椒/蛋白质宿主 - 甘油系统和全长蛋白的二级和三级结构的影响。使用来自模型系统的数据，将开发新的Pyrosetta程序，以预测硫酰胺对蛋白质稳定性的影响。这些预测将在含硫酰胺的蛋白质上进行测试，该蛋白将通过X射线晶体学和/或NMR以及溶液相稳定性测量值来表征。综上所述，这些实验有望提供对硫酰胺对硫酰胺对蛋白质特性从基于本地序列效应的影响的影响，从基于本地序列的效果到对次级，第三级甚至第四纪结构的影响。该奖项反映了NSF的法定任务，并通过使用该基金会的智力功能和广泛的影响来评估NSF的法定任务。