Date of Award

4-21-2009

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

First Advisor

Dr. Zhen Huang - Chair

Second Advisor

Dr. David W. Wilson

Third Advisor

Dr. Al Baumstark

Fourth Advisor

Dr. Lucjan Strekowski

Abstract

Nucleic acids play important roles in living systems by storing and transferring genetic information and directing protein synthesis. Recently, it was found that nucleic acids can catalyze chemical and biochemical reactions similar to protein enzymes. In addition, they can also serve as drug targets for the treatment of deadly diseases such as AIDS and cancers. As a result, the 3D structure study of nucleic acids and proteinnucleic acids complexes by X-ray crystallography has become one of the most active research areas. However, the two intrinsic bottlenecks of macromolecule X-ray crystallography, including crystallization and phase determination, have significantly limited its application in study and discovery of the new structures and folds, as well as in exploration of the biological mechanisms. So far, the selenium derivatization (Se-Met) of proteins and multiple anomalous dispersion (MAD) or single anomalous dispersion (SAD) technology have revolutionized the protein crystallography field by providing a rational solution to solve the phase determination problem. Similarly, it’s important and urgent to develop a corresponding methodology for nucleic acid X-ray crystallography. The work presented here includes two general research directions: the selenium derivatized nucleic acids (SeNA) and tellurium derivatized nucleic acids (TeNA): 1) The SeNA strategy by site-specifically replacing oxygen with selenium at the 2’ and 4 positions of thymidine and uridine has been developed. We found that the selenium derivatization at both sites are relatively stable and doesn’t cause significant structure perturbations by comparing with their corresponding native counterparts. In addition to the phase determination, the 2’-Se modification can also facilitate crystal growth of many oligonucleotides. Moreover, we have observed colorful DNAs and RNAs with the 4-Se modification for the first time. 2) The TeNA strategy by covalently incorporating tellurium functionalities into different positions of nucleic acids, particularly at the 2’ and 5 position of thymidine, has been developed. We have demonstrated the compatibility of the tellurium modification and solid-phase synthesis, as well as the potential application of the tellurium modifications in anti-viral drug synthesis and DNA-damage investigation.

Included in

Chemistry Commons

Share

COinS