Through‐Space/Through‐Bond Energy Decomposition Analysis Clarifies the Mechanism of Transition Mutation in DNA Containing O6‐Methylguanine Lesion

In this work, we advance the previously developed Through-Space/Through-Bond (TS/TB) orbital interaction analysis and extend it to a new Through-Space/Through-Bond Energy Decomposition Analysis (TS/TB-EDA). These methods are applied to investigate the mechanism behind the transition mutation from guanine:cytosine (G:C) to adenine:thymine (A:T) in DNA containing O6-methylguanine (O6-MeG) lesions. The mutagenicity of O6-MeG has long been debated, with various geometric and energetic factors proposed. Using TS/TB and TS/TB-EDA, we compare the electronic structures of damaged and undamaged base pairs at the mutation site during DNA replication, emphasizing the energetic components that influence base pair binding. Our analysis explores the strengths of individual orbital interactions, such as <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:semantics><mml:mrow><mml:mi>π</mml:mi></mml:mrow> <mml:annotation>$$ \pi $$</mml:annotation></mml:semantics> </mml:math> -bonds and hydrogen bonds, as well as decomposes the total binding energy between DNA bases into the physical components. We find that the electronic structure of the O6-MeG lesion closely resembles that of A rather than G, while the O6-MeG:T pair exhibits energetic and geometric characteristics similar to A:T. This similarity suggests the explanation for the polymerase's preference for pairing O6-MeG with T. The obtained results are consistent with experimental data and provide insights into the high O6-MeG:T mismatch rate observed in O6-MeG damaged DNA sequences.