A library approach to investigate the correlation between peptide rigidity and binding affinity

研究肽刚性和结合亲和力之间相关性的库方法

• 批准号: 1904872
• 负责人: Matthew Hartman
• 金额: $ 45万
• 依托单位: Virginia Commonwealth University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1904872&HistoricalAwards=false
• 关键词: library; approach; investigate; correlation; between

The ability of a peptide to serve as an inhibitor depends on the affinity for its targeted protein. With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Dr. Matthew Hartman at Virginia Commonwealth University and Dr. Irene Chen at University of California-Santa Barbara to investigate how the molecular rigidities of peptides determine their binding affinities to proteins. This project uses new and powerful technologies to create molecular collections, or libraries, containing trillions of molecules with diverse ranges of defined rigidities. These peptide libraries are tested for their affinities to proteins with rigid binding pockets or with more flexible binding surfaces. The resulting trends will streamline the discovery of peptide molecules that inhibit biologically and clinically important proteins. This project provides opportunities for interdisciplinary research training and career mentoring to a diverse population of graduate and undergraduate students, including students from underrepresented minority groups. In addition, a module is developed that uses Lego construction toys to introduce upper elementary students to the concept and power of molecular diversity.Peptide libraries are powerful storehouses for the development of protein ligands and inhibitors of protein-protein interactions; molecules that are scarce in standard small molecule libraries. This project addresses the potential benefits of introducing conformational constraints into peptide libraries to answer two questions about the relationship of peptide flexibility and target affinity: does rigidification inherently improve binding affinity; and, are high-affinity binders with rigid structures more rare compared to flexible structures of similar affinity within a library? To answer these questions, peptide libraries are created with matched hydrophobicity and sequence diversity, but increasing levels of rigidity. These libraries will be tested against streptavidin (with a compact and rigid binding site and that recognizes contiguous amino acid motifs), and a prototypical SH3 domain (with an extended and flexible binding surface) to study the dependence on the structure of the protein targets. This wholesale analysis of the prevalence of binders and affinities of peptides selected from each library answers the guiding questions concerning the relationship of rigidity to affinity. Dr. Hartman through this project provides training in chemical biology to a diverse group of undergraduate and graduate students at Virginia Commonwealth University. He and his group are also developing the Plickers-based activities to engage elementary school students (including those from underrepresented minority groups) in learning about molecular interactions and mechanisms.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.

多肽作为抑制物的能力取决于与其目标蛋白的亲和力。该奖项将资助弗吉尼亚联邦大学的马修·哈特曼博士和加州大学圣巴巴拉分校的艾琳·陈博士研究多肽的分子刚性如何决定其与蛋白质的结合亲和力。该项目使用新的和强大的技术来创建分子集合或库，其中包含具有不同定义刚性范围的数万亿个分子。测试这些多肽文库与具有刚性结合口袋或具有更灵活结合表面的蛋白质的亲和力。由此产生的趋势将简化对抑制生物和临床重要蛋白质的多肽分子的发现。该项目为不同群体的研究生和本科生提供跨学科研究培训和职业指导的机会，包括来自代表性不足的少数群体的学生。此外，还开发了一个模块，使用乐高建筑玩具向高年级学生介绍分子多样性的概念和力量。多肽库是开发蛋白质配体和蛋白质相互作用的抑制剂的强大仓库，这些分子在标准小分子库中是稀有的。该项目解决了将构象限制引入多肽库以回答关于多肽灵活性和靶亲和力关系的两个问题的潜在好处：硬化性是否固有地提高了结合亲和力；以及，与库中具有类似亲和力的柔性结构相比，具有刚性结构的高亲和力结合物是否更稀有？为了回答这些问题，创建的多肽文库具有匹配的疏水性和序列多样性，但增加了刚性水平。这些文库将与链霉亲和素(具有紧凑和刚性结合部位，并识别连续的氨基酸基序)和典型的SH3结构域(具有延伸和灵活的结合表面)进行测试，以研究对蛋白质靶标结构的依赖。这种对从每个文库中选择的多肽的结合剂和亲和力的流行程度的批发分析回答了关于刚性与亲和力的关系的指导性问题。哈特曼博士通过这个项目为弗吉尼亚联邦大学的不同本科生和研究生提供化学生物学方面的培训。他和他的团队还在开发基于Plickers的活动，以吸引小学生(包括那些来自代表不足的少数群体的学生)学习分子相互作用和机制。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势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

Spontaneous, co-translational peptide macrocyclization using p -cyanoacetylene–phenylalanine

使用对氰基乙炔苯丙氨酸进行自发共翻译肽大环化

• DOI: 10.1039/d2cc01148d
• 发表时间: 2022
• 期刊: Chemical Communications
• 影响因子: 4.9
• 作者: Franco, H. Estheban;Chaloux, Brennan T.;Hartman, Matthew C.
• 通讯作者: Hartman, Matthew C.