Effect of polarization and charge on biological halogen bonds

该奖项由化学部门的生命过程化学项目颁发。来自科罗拉多州立大学的Pui S. Ho和Anthony K. Rappe将描述生物系统中卤素键（x键）的几何能量关系，并从这些关系中推导出精确模拟卤素键（x键）的方法。x键是重要的非共价相互作用，确定了许多抑制剂对其蛋白质靶标的特异性。假设是x键在抑制剂设计中未被充分利用，因为我们对它们的几何形状如何定义它们的能量的理解不完全。这项研究的长期目标是开发一套势能函数来描述x键，从生物分子相互作用的几何能量关系的广泛表征开始。为了实现这些目标，研究人员将比较T4溶菌酶中卤素x键供体的极化和x键受体的电荷对DNA连接中x键结构和能量的影响。他们还将研究这些物理化学效应如何促进配体结合，使用一组溶菌酶结构，在蛋白质的不同位置设计人工口袋。最后，他们将开发量子化学方法来模拟实验结构-能量关系。实验结果和量子力学结果最终将被整合到生物x键的新势能函数中，该函数可以被纳入用于生物分子建模的分子力学力场中。这项研究项目的成果可能会影响新型药物的计算机辅助设计。我们还将努力将研究与科学教育结合起来，利用研究部分产生的科学问题来指导与物理生物化学课程所教授的基本原理相关的课堂项目。最后，该项目整合了实验和理论方法来表征独特的分子相互作用，预计将继续为结构生物学和生物化学领域的博士后学员、研究生和本科生（包括女性和不同背景的学生）提供广泛的培训。

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.