IIIT Hyderabad Publications
Urea Mimics Nucleobases by Preserving the Helical Integrity of B-DNA Duplexes via Hydrogen Bonding and Stacking Interactions
Author: Indrajit Patil
Report no: IIIT/TH/2016/41
Advisor:U Deva Priyakumar
One of the DNA lesions formed due to free radical damage of thymine is urea, occurrence of which in DNA blocks DNA polymerases, and has been shown to be lethal. Recently, it has been shown that urea is capable of forming hydrogen bonding and stacking interactions with nucleobases, which are responsible for the unfolding of RNA in aqueous urea. Base pairing and stacking are inherent properties of nucleobases; since urea is able to form both, this study attempts to investigate if urea can mimic nucleobases in the context of the nucleic acid structures by examining the effect of introducing urea lesions complementary to the four different nucleobases on the overall helical integrity of B-DNA duplexes and their thermodynamic stabilities using molecular dynamics (MD) simulations. The MD simulations resulted in stable duplexes without significant changes in the global B-DNA conformation. In agreement with experimental results, the urea lesions occupy intrahelical positions by forming hydrogen bonds with nitrogenous nucleobases. Further, these urea lesions form hydrogen bonding and stacking interactions with other nucleobases of the same and partner strands, which are sometimes similar to the nucleobases in typical B-DNA duplexes. Direct hydrogen bond interactions are observed for the urea-purine pairs within DNA duplexes, whereas two different modes of interactions, namely direct hydrogen bonds and water-mediated hydrogen bonds, are observed for the urea-pyrimidine pairs. The latter explains the complexities involved in interpreting the experimental NMR data reported previously. Binding free energy calculations were further performed to understand the thermodynamic stability of the urea incorporated DNA duplexes with respect to pure duplexes. This study suggests that urea potentially mimics nucleobases by pairing opposite to all the four nucleobases and maintains the overall structure of the B-DNA duplexes.
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Centre for Computational Natural Sciences and Bioinformatics
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