H-Bonding Control of Molecular Self Assembly

分子自组装的氢键控制

• 批准号: 0750357
• 负责人: Andrew Hamilton
• 金额: $ 54.86万
• 依托单位: Yale University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-15 至 2011-01-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0750357&HistoricalAwards=false
• 关键词: Bonding; Control; Molecular; Self; Assembly

With this award from the Organic and Macromolecular Chemistry Program, Prof. Andrew Hamilton will pursue the goal to develop strategies that exploit hydrogen bonding as a means of controlling molecular self-assembly. This represents an approach in which defined molecular shapes and interactions are built synthetically into individual components that then can self-assemble into a more complex aggregate. Most importantly the aggregate should possess properties and characteristics that are not present in the individual components. In the proposed project they will extend this approach to self-assembly particularly in aqueous solution with emphasis on targeting biological molecules. Their principal strategy will use the complementarity present in strands of DNA oligonucleotides as a way of bringing together organic fragments into aggregates that possess the property of biomolecule recognition. In this way they will be able to control the structure, stoichiometry and potential function of these aggregates through the chosen sequence and self-assembling properties of the oligonucleotides. Within this overall goal they will have three broad specific aims:1- To use oligonucleotide aggregates on the cusp of stability to detect proteins.Complementary and fluorophore functionalized oligonucleotide strands that barely form a duplex under normal conditions will be stabilized by attaching physiologically important hydrophobic molecules (e.g. estrone, testosterone and other steroids). In the presence of the target protein (e.g. estrogen receptor) the stabilizing group will be sequestered, the duplex will dissociate and a fluorescent signal will be detected. 2- To develop bidentate protein binding agents self-assembled on duplex DNA.They will further investigate the use of DNA duplex as a scaffold for the formation of dynamic combinatorial libraries of protein binding agents. Attachment of two organic fragments onto the 3'- and 5'-ends of complementary DNA strands leads to the positioning of those fragments at one end of the duplex capable of targeting a protein surface. 3- To develop tetradentate protein binding agents self-assembled on quadruplex DNA.They will extend this approach to aggregates that present larger surface areas and that can target the exterior surface of proteins through the use of DNA quadruplexes. They will target these aggregates to tetrameric proteins such as neuraminidase and concanavolin-A.Broader Impacts - This work represents a new direction in chemistry, taking it not only into greater control of large molecular structures and their properties but also into aqueous environments and potential novel applications in biosensor design and protein binding agents. Students will gain broad experience in molecular design, synthesis, biochemistry and analysis of physicochemical properties. The PI has trained more than 110 student and post-doctoral coworkers and always has been deeply committed to the principles and practices of diversity. In recent years this has translated into a research group that has comprised, on average, around 50% of women and underrepresented minority students and post-docs. In his responsibilities as Provost of Yale, he has supported and initiated many programs for minority science students as well as broad initiatives focused on increasing the diversity of faculty, students and staff at Yale.

凭借有机和高分子化学项目的这一奖项，安德鲁·汉密尔顿教授将追求开发利用氢键作为控制分子自组装手段的策略的目标。这代表了一种方法，其中定义的分子形状和相互作用被综合构建成单个组件，然后这些组件可以自组装成更复杂的聚集体。最重要的是，骨料应具有单个组件所不具备的性能和特征。在拟议的项目中，他们将把这种方法扩展到自组装，特别是在水溶液中，重点是针对生物分子。他们的主要策略将利用 DNA 寡核苷酸链中存在的互补性，将有机片段聚集成具有生物分子识别特性的聚集体。 通过这种方式，他们将能够通过寡核苷酸的所选序列和自组装特性来控制这些聚集体的结构、化学计量和潜在功能。在这个总体目标中，他们将有三个广泛的具体目标：1-使用处于稳定性尖端的寡核苷酸聚集体来检测蛋白质。在正常条件下几乎不形成双链体的互补和荧光团功能化寡核苷酸链将通过附着生理上重要的疏水分子（例如雌酮、睾酮和其他类固醇）来稳定。在目标蛋白（例如雌激素受体）存在的情况下，稳定基团将被隔离，双链体将解离并且将检测到荧光信号。 2-开发在双链体DNA上自组装的双齿蛋白质结合剂。他们将进一步研究使用DNA双链体作为形成蛋白质结合剂动态组合文库的支架。 将两个有机片段附着到互补 DNA 链的 3' 和 5' 端，导致这些片段定位在能够靶向蛋白质表面的双链体的一端。 3-开发在四链体 DNA 上自组装的四齿蛋白结合剂。他们将这种方法扩展到具有更大表面积的聚集体，并且可以通过使用 DNA 四链体靶向蛋白质的外表面。他们将这些聚集体靶向四聚体蛋白质，例如神经氨酸酶和伴刀豆素-A。 更广泛的影响 - 这项工作代表了化学的新方向，不仅可以更好地控制大分子结构及其特性，还可以进入水环境以及生物传感器设计和蛋白质结合剂中的潜在新应用。 学生将获得分子设计、合成、生物化学和理化性质分析方面的广泛经验。 PI 已培训了 110 多名学生和博士后同事，始终坚定致力于多元化的原则和实践。 近年来，这已转化为一个研究小组，平均由约 50% 的女性以及代表性不足的少数族裔学生和博士后组成。在担任耶鲁大学教务长期间，他支持并发起了许多针对少数族裔理科学生的项目，以及旨在提高耶鲁大学教师、学生和工作人员多样性的广泛举措。