Towards Functional Metal-Mediated DNA Base-Pairs

通过这一奖项，化学部生命过程化学项目资助加州大学河滨分校的Christopher Switzer博士开发能够与天然碱基对一起参与信息传递反应的金属介导的碱基对。为了实现这一目标，金属介导的碱基对基序将被开发出具有最佳形状和大小的可被天然酶接受的基序。该奖项下的工作将建立在PI实验室的初步研究基础上，以创造能够实现这种功能的下一代金属介导的碱基对。这一新一代碱基对使用三齿类嘌呤成分和单齿类嘧啶成分来配位二价金属离子，如Cu2+。金属介导的具有天然聚合酶的碱基对的功能将通过使用一系列不同的单齿核苷酸来探索和优化，这些核苷酸是根据合成的便利性和已知的最佳设计特征选择的。Watson-Crick碱基对编码所有生物体的遗传信息。虽然天然碱基对依赖氢键进行识别，但其他弱或可逆的相互作用有望产生非标准碱基对。最近有研究表明，金属介导键可以取代DNA螺旋中非标准碱基之间的氢键。因此，实现金属介导的功能性碱基对的下一步步骤现在已经触手可及。该研究计划将为化学生物学研究生提供坚实的培训基础。此外，在建议期间，将为本科生提供研究机会，包括为代表性不足的少数族裔或女性提供暑期本科生研究职位。

With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Dr. Christopher Switzer at the University of California-Riverside, to develop metal mediated base pairs that are capable of participating in information transfer reactions alongside their natural counterparts. To accomplish this objective, metal mediated base pair motifs will be developed with optimal shape and size for acceptance by natural enzymes. The work under the award will build on preliminary studies by the PI's laboratory to create a next generation metal mediated base pair capable of such function. This next generation base pair uses a tridentate purine-like component and a monodentate pyrimidine-like component to coordinate a divalent metal ion, such as Cu2+. The function of metal mediated base pairs with natural polymerase enzymes will be explored and optimized by employing a range of different monodentate nucleotides chosen on the basis of synthetic expediency and known optimal design features.Watson-Crick base pairs encode genetic information in all organisms. While natural base pairs rely on hydrogen bonds for recognition, other weak or reversible interactions hold promise for the creation of non-standard base pairs. Metal-mediated bonds have been shown recently to replace hydrogen bonds between non-standard bases in the DNA helix. The next steps in the progression to achieve functional metal-mediated base pairs are therefore now within reach. The program of study will provide a solid training ground for graduate students in chemical biology. Additionally, research opportunities for undergraduate students will be offered during the proposal period, including a summer undergraduate research position for underrepresented minorities or women.