Atom-specific Selenium Derivatization of Nucleic Acids for Crystallization and Structure Studies

智能优点：X射线结晶学是在原子水平上确定和研究核酸和蛋白质-核酸络合物三维结构的最佳方法之一。这些研究为核酸的功能和机制提供了新的见解。本项目的课题组通过用Se原子特异性地取代核酸中的氧，开创和发展了针对核酸重原子衍生化和结晶的Se修饰，这是核酸X射线结晶学的两大挑战/瓶颈。该项目成功地展示了硒衍生化用于分相，并通过核酸的2‘-Se衍生化发现了结晶促进作用。目前的研究项目包括对DNA和RNA进行进一步的X射线结晶学研究，以期为标准重原子衍生化和物相确定提供可行的合理解决方案，以及促进结晶的潜在解决方案。这一研究项目的智力价值在于为分子相互作用、堆积、结晶机制、晶体生长促进以及硒衍生的DNA和RNA以及相应的天然核酸的结构提供了新的见解。此外，还将开发新的合成路线，将Se引入DNA和RNAs的多个位置，用于功能和晶体结构的研究。研究的更广泛影响：这项研究项目将显著扩大关于核酸的科学知识，导致新材料和应用，允许更广泛地获得这些有价值的新材料和独特的分子，以及吸引公众的注意。这个研究小组将接触到研究性非密集型大学和高中的教职员工，并邀请他们参与这个研究项目。外展和研究机会将有助于提高公众的认识和科学素养。此外，许多学生，特别是代表不足的少数民族学生，将通过参与这一项目在动手实验研究和科学交流技能方面得到培训。佐治亚州立大学(GSU)化学系有着培养和服务本科生和研究生，特别是少数族裔学生的深厚传统。该项目将提供各种广泛的多学科培训机会，并在华盛顿州立大学化学系和生物系的研究培训中产生协同效应。

Intellectual Merit: X-ray crystallography is one of the best methods for the determination and study of 3-D structures of nucleic acids and protein-nucleic acid complexes at the atomic level. Such studies provide novel insights into nucleic acid functions and mechanisms. Via atom-specific substitution of nucleic acid oxygen with selenium, the research group on this project has pioneered and developed the selenium modification for nucleic acid heavy atom derivatization and crystallization, which are the two major challenges/bottlenecks in nucleic acid X-ray crystallography. This project has led to a successful demonstration of the utility of selenium derivatization for phasing, and to the discovery of crystallization facilitation by the 2'-Se derivatization of nucleic acids. The current research project involves further X-ray crystallographic studies on DNAs and RNAs in order to provide a viable rational solution for standard heavy atom derivatization and phase determination, as well as a potential solution for crystallization facilitation. The intellectual merit of this research project is in providing new insights into molecular interactions, packing, crystallization mechanisms, crystal growth facilitation, as well as structures of the Se-derivatized DNAs and RNAs and the corresponding natural nucleic acids. In addition, new synthetic routes to introduce Se into multiple positions of DNAs and RNAs will be developed for function and crystal structure studies. Broader Impact of the Research: This research project will significantly enlarge scientific knowledge on nucleic acids, lead to novel materials and applications, allow broader access to these valuable new materials and unique molecules, as well as attract the attention of the general public. This research group will reach out to faculty members in research non-intensive colleges and high schools, and invite them to participate in this research project. The outreach and research opportunities will help to raise the awareness and scientific literacy of the general public. Moreover, many students, especially underrepresented minority students, will be trained through participation in this project in hands-on experimental research, and scientific communication skills. The Chemistry Department at Georgia State University (GSU) has a strong tradition of educating and serving undergraduate and graduate students, especially underrepresented minority students. This project will offer various extensive multi-disciplinary training opportunities and generate synergy in research training in both Chemistry and Biology Departments at GSU.