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Uracil is a common DNA lesion which is recognized and removed by uracil DNA-glycosylase (UDG) as a part of the base excision repair pathway. Excision proceeds by base flipping, and UDG efficiency is thought to depend on the ease of deformability of the bases neighboring the lesion. We used molecular dynamics simulations to assess the flexibility of a large library of dsDNA strands, containing all tetranucleotide motifs with U:A, U:G, T:A or C:G base pairs. Our study demonstrates that uracil damaged DNA largely follows trends in flexibility of undamaged DNA. Measured bending persistence lengths, groove widths, step parameters and base flipping propensities demonstrate that uracil increases the flexibility of DNA, and that U:G base paired strands are more flexible than U:A strands. Certain sequence contexts are more deformable than others, with a key role for the 30 base next to uracil. Flexibilities are large when this base is an A or G, and repressed for a C or T. A 50 T adjacent to the uracil strongly promotes flexibility, but other 50 bases are less influential. DNA bending is correlated to step deformations and base flipping, and bending aids flipping. Our study implies that the link between substrate flexibility and UDG efficiency is widely valid, helps explain why UDG prefers to bind U:G base paired strands, and suggests that the DNA bending angle of the UDG-substrate complex is optimal for base flipping.
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Why do A·T and G·C self-sort? Hückel aromaticity as a driving force for electronic complementarity in base pairing
Density functional theory computations and block-localized wavefunction analyses for 57 hydrogen-bonded base pairs document excellent linear correlation between the gas-phase association energies and the degree of aromaticity gain of paired bases ( r = 0.949), challenging prevailing views of factors that underlie the proposed electronic complementarity of A·T(U) and G·C base pairs. Base pairing interactions can polarize the π-electrons of interacting bases to increase (or decrease) cyclic 4 n + 2π electron delocalization, resulting in aromaticity gain (or loss) in the paired bases, and become strengthened (or weakened). The potential implications of this reciprocal relationship for improving nucleic acid force-fields and for designing robust unnatural base pairs are discussed.
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- Award ID(s):
- 1751370
- PAR ID:
- 10081327
- Date Published:
- Journal Name:
- Organic & Biomolecular Chemistry
- ISSN:
- 1477-0520
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1039/C8OB01669K
