Enhanced Nuclear Quantum Effects in Radical Cationic Adenine-Thymine Base Pairs

Proton-transfer reactions in DNA base pairs have long been discussed in relation to tautomer formation and mismatch generation during DNA replication. In this study, nuclear quantum effects (NQEs) on neutral and radical cationic adenine-thymine (A-T) base pairs were investigated using classical molecular dynamics (CLMD) and path integral molecular dynamics (PIMD) simulations at the (U)-ωB97XD/6-31G** level. For the neutral A-T pair, NQEs mainly affected covalent bond lengths, whereas intermolecular hydrogen-bond distances were only weakly influenced. For the radical cationic A-T⁺ pair, NQEs instead manifested primarily as a broadening of the proton-transfer distribution and a qualitative reshaping of the free-energy profile. Specifically, the double-well profile obtained with CLMD changed into a broad single-well-like profile in PIMD, accompanied by substantial proton delocalization between adenine and thymine. These results indicate that cationization markedly amplifies NQEs and promotes access to proton-shared and tautomer-like configurations in A-T base pairs.