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

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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.