Effect of polarization and charge on biological halogen bonds

极化和电荷对生物卤素键的影响

• 批准号: 1152494
• 负责人: Pui Ho
• 金额: $ 45万
• 依托单位: Colorado State University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-15 至 2016-01-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1152494&HistoricalAwards=false
• 关键词: Effect; polarization; charge; biological; halogen

In this award from the Chemistry of Life Processes Program in the Chemistry Division, Drs. Pui S. Ho and Anthony K. Rappe, from Colorado State University, will characterize the geometry-energy relationships of, and derive from these relationships methods to model halogen bonds (X-bonds) accurately in biological systems. X-bonds are important non-covalent interactions in defining the specificity of many inhibitors to their protein targets. The hypothesis is that X-bonds are underutilized in inhibitor design, because of our incomplete understanding for how their geometries define their energies. The long-term goal of the research is to develop a set of potential energy functions to describe X-bonds, starting with extensive characterization of the geometry-energy relationships for the interactions in biological molecules. To accomplish these goals, the researchers will compare the effects of polarization of the halogen X-bond donor and the charge of the X-bond acceptor on the structure and energies of X-bonds in DNA junctions in T4 lysozyme. They will also study how these physicochemical effects contribute to ligand binding using a set of lysozyme constructs with artificial pockets engineered at various sites in the protein. Finally, they will develop quantum chemical methods to model the experimental structure-energy relationships. The experimental and quantum mechanical results will eventually be integrated to develop new potential energy functions for biological X-bonds that can be incorporated into molecular mechanics force fields that are used in biomolecular modeling.The outcomes of this research project are likely to impact the computer-aided design of new classes of drugs. Efforts will also be made to integrate research with science education, by using scientific problems derived from the research component to guide class projects related to the basic principles taught in a Physical Biochemistry course. Finally, this project, which integrates experimental and theoretical methods to characterize unique molecular interactions, is expected to continue to provide a diverse group of postdoctoral trainees, graduate and undergraduate students (including women and students of diverse backgrounds) with broad training in the areas of structural biology and biological chemistry.

在这个奖项从生命过程的化学计划在化学部，裴S。作者：Anthony K.来自科罗拉多州立大学的Rappe将描述生物系统中卤键（X键）的几何能量关系，并从这些关系中推导出精确建模卤键（X键）的方法。X-键是重要的非共价相互作用，在定义许多抑制剂的特异性，其蛋白质的目标。假设是X键在抑制剂设计中未得到充分利用，因为我们不完全理解它们的几何形状如何定义它们的能量。这项研究的长期目标是开发一套势能函数来描述X键，首先是广泛表征生物分子相互作用的几何能量关系。为了实现这些目标，研究人员将比较卤素X-键供体的极化和X-键受体的电荷对T4溶菌酶中DNA结中X-键的结构和能量的影响。他们还将研究这些物理化学效应如何有助于使用一组溶菌酶构建体与蛋白质中不同位点的人工口袋结合。最后，他们将开发量子化学方法来模拟实验结构-能量关系。实验和量子力学结果最终将被整合，以开发生物X键的新势能函数，这些函数可以被纳入用于生物分子建模的分子力学力场中。该研究项目的结果可能会影响计算机辅助设计新型药物。还将努力将研究与科学教育相结合，通过使用来自研究部分的科学问题来指导与物理生物化学课程中教授的基本原则相关的课堂项目。最后，这个项目，它整合了实验和理论方法来表征独特的分子相互作用，预计将继续提供一个多元化的博士后学员，研究生和本科生（包括妇女和不同背景的学生）在结构生物学和生物化学领域的广泛培训。