药学前沿大讲堂95讲-Creating Novel Nucleic Acid Base Pairs with Higher Fidelity Than the Nature

题目：Creating Novel Nucleic Acid Base Pairs with Higher Fidelity Than the Nature

报告人：Zhen Huang (黄震), Ph.D 

Department of Chemistry & Department of Biology, Georgia State University,

主持人：黄志纾 教授

        bm11222宝马娱乐网站

时间：2011年7月28日下午2：00

地点：中山大学东校区bm11222宝马娱乐网站112会议室

报告简介：

The base pairs are the contributors to the sequence-dependent recognition of nucleic acids, genetic information storage, as well as to high fidelity of DNA polymerase replication. However, the wobble base pairing, where T pairs with G instead of A, reduces specific base-pairing recognition and compromises high fidelity of the enzymatic polymerization. Via the selenium atomic probing at the 2-position of thymidine and uridine, we have investigated the wobble discrimination by manipulating the steric and electronic effects at the 2-exo position, providing a unique chemical strategy to enhance the base pair specificity. We first synthesized the novel 2-Se-thymidine (SeT) and 2-Se-uridine (SeU) derivatives, phosphoramidites, and the Se-DNAs and Se-RNAs. Our biophysical and structural studies of the 2-Se-T DNAs and Se-RNAs reveal that the bulky 2-Se atom with weak hydrogen-bonding ability can largely increase mismatch discriminations (including T/G and U/G wobbles and T/C mismatched base pairs) while maintaining the SeT/A and SeU/A virtually identical to the native T/A base pair. The 2-Se atom bulkiness and the electronic effect are probably the main factors responsible for the discrimination against formation of the wobble SeT/G and SeU/G base pairs. Our investigations provide a potential novel tool to investigate the specific recognition of base pairs, which is the basis of high fidelity during replication, transcription and translation. Furthermore, this Se-atom-specific substitution and probing are useful for X-ray crystal structure and function studies of nucleic acids and protein-nucleic acid complexes.