Conformational flexibility and base-pairing tendency of the tobacco carcinogen O6-[4-oxo-4-(3-pyridyl)butyl]guanine

•The POB-G DNA adduct displays a high degree of intrinsic conformational flexibility.•A stable non-distorted POB-G:T pair explains observed G ➔ A mutations.•Slightly distorted POB-G Watson-Crick face and A/C pairs clarify less common pairs.•Lack of G insertion opposite POB-G is related to highly distorted POB-G:G pairs.

The present work uses DFT calculations to characterize the conformational and hydrogen-bonding properties of O6-[4-oxo-4-(3-pyridyl)butyl]guanine (POB-G), a DNA adduct caused by tobacco. POB-G is found to adopt many isoenergetic conformations that allow for discrete interactions between the bulky moiety and the adducted G and/or pairing base. The calculated structure and stability of the hydrogen-bonded pairs between the Watson-Crick or Hoogsteen face of POB-G and the canonical DNA nucleobases fully rationalize the previously reported mutational spectra. Specifically, the stable, non-distorted pseudo-Watson-Crick POB-G:T pair explains the predominant G ➔ A mutations, while the stable, yet marginally distorted pairs between the Watson-Crick face of POB-G and A or C clarify the G ➔ T mutations and non-mutagenic replication. Finally, the stable, yet highly distorted Hoogsteen POB-G:G pair rationalizes the experimentally-observed insertion but lack of persistence of G opposite POB-G in DNA. Overall, these structural insights are critical for guiding future studies that strive to fully understand the adduct mutagenicity, including the accessible conformations and the replication of POB-G-adducted DNA.

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