Computational insights into the mutagenicity of two tobacco-derived carcinogenic DNA lesions

Area of Science:

• Chemical Biology
• Computational Chemistry
• Molecular Toxicology

Background:

• Tobacco carcinogens, such as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, induce DNA damage.
• Key DNA lesions include O6-[4-oxo-4-(3-pyridyl)butyl]guanine (POB-G) and O6-[4-hydroxy-4-(3-pyridyl)butyl]guanine (PHB-G).
• Subtle chemical differences in bulky moieties can alter biological outcomes of DNA adducts.

Purpose of the Study:

• To investigate the conformational and base-pairing preferences of POB-G and PHB-G using a multiscale computational approach.
• To elucidate the structural basis for the mutagenicity of these tobacco-derived DNA lesions.
• To compare the mutagenic potential of PHB-G relative to POB-G.

Main Methods:

• Multiscale computational modeling was employed to study DNA lesions.
• Calculations focused on intrinsic conformational preferences and base-pairing of POB-G and PHB-G.
• Analysis included lesion properties within DNA and the polymerase η active site.

Main Results:

• Both POB-G and PHB-G form stable base pairs with cytosine (C) and thymine (T).
• The T pairs exhibit the least distortion compared to canonical DNA, aligning with experimental data for POB-G.
• PHB-G is predicted to be more mutagenic than POB-G due to enhanced stability of the PHB-G:T pair and a propensity for intercalated DNA conformations.

Conclusions:

• Computational models successfully rationalize experimental mutagenicity profiles of POB-G.
• Structural differences in the bulky moiety explain the increased mutagenicity of PHB-G.
• This study provides mechanistic insights into tobacco-induced DNA damage and mutagenesis.