Zinc Fingers as Templates for Metal Complex Interactions

DNA被一组统称为锌指的蛋白质以极高的特异性识别。DNA-锌指相互作用具有重要的生物学后果，例如当细胞分裂或病毒繁殖时。拟议的实验将探索一种新发现的方法，使用首席研究员实验室中发现的含金属化合物(特别是铂)来破坏相互作用。未来将进行研究，以了解和控制这一特性，以开发新的药物，如抗病毒(特别是艾滋病毒)化合物。这种方法将是实验的(化学和生物的)和理论的(计算的)。该项目是一个很好的例子，说明了基础研究和发现与重要的社会效益之间的联系。这项研究项目也将是国际合作的一部分，让研究生接触到这个主题和跨文化体验。通过这个奖项，化学系的生命过程化学计划资助弗吉尼亚联邦大学的Nicholas Farrell博士，通过系统研究官能化配位化合物对锌置换和蛋白质结构和功能破坏的动力学和热力学的立体和电子效应来表征锌指蛋白质的反应。具体的焦点将集中在HIV NCp7核衣壳蛋白(NC)上，并将通过中断NC-RNA(DNA)的相互作用来研究铂-金属碱基作为核衣壳-核酸拮抗剂的机制。通过增强的pi-pi，金属碱基和含色氨酸的核衣壳之间的堆积，影响选择性的“非共价”配体-生物分子识别的因素将被研究。其次，这种识别会导致“共价”金属-硫代键的形成和随后的锌排出。我们将探索弱“有机”和“无机”亲电体的类比，以设计特定的相互作用，区分不同的Cys2His2，Cys3His和Cys4锌指结合部位。

DNA is recognized with exquisite specificity by a group of proteins collectively known as zinc fingers. The DNA-zinc finger interaction has important biological consequences, for example when cells divide or viruses multiply. The proposed experiments will explore a newly discovered means for disrupting the interaction using metal containing compounds (specifically platinum) discovered in the laboratory of the principal investigator. Future research will be conducted to understand and control this property for the development of new medicines like anti-viral (especially HIV) compounds. The approach will be both experimental (chemical and biological) and theoretical (computational). The project represents an excellent example of the linkage between basic research and discovery on one hand, and important societal benefits on the other. The research project will also be part of an international collaboration exposing graduate students to the subject, and to cross-cultural experiences.With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Dr. Nicholas Farrell from Virginia Commonwealth University to characterize reactions of zinc finger proteins by the systematic study of steric and electronic effects of functionalized coordination compounds on the kinetics and thermodynamics of zinc displacement and disruption of protein structure and function. A specific focus will be on the HIV NCp7 nucleocapsid protein (NC), and the mechanism of platinum-metal nucleobases as nucleocapsid-nucleic acid antagonists through interruption of the NC-RNA(DNA) interaction will be examined. The factors affecting selective "non-covalent" ligand-biomolecule recognition through enhanced pi-pi; stacking between metallated nucleobases and the tryptophan-containing nucleocapsid will be examined. Secondly, such recognition can lead to formation of the "covalent" metal-thiolate bond and subsequent zinc ejection. We will explore the analogy of weak "organic" and "inorganic" electrophiles to design specific interactions differentiating the distinct Cys2His2, Cys3His and Cys4 zinc finger-binding sites.