Quantum chemical study of the hydrogen‐bonded patterns in A · T base pair of DNA: Origins of tautomeric mispairs,base flipping,and Watson–Crick ⇒ Hoogsteen conversion

The current work aims to thoroughly investigate a variety of facets of the hydrogen‐bond pattern of the Watson–Crick A · T base pair of DNA. It offers a novel mechanism of the origin of the hydrogen‐bonded mispairing in the A · T base pair based on the analysis of the lower‐energy portion of the total potential energy surface of all possible rearrangements of the hydrogen‐bond patterns in this pair, performed at the Hartree–Fock (HF), second‐order Moller–Plesset (MP2)//HF, and B3LYP computational levels in conjunction with 6‐31+G(d) basis set. The specific novelty of this mechanism is that the primary step consists of a single proton transfer along the N₃(T)–H … N₁ (A) hydrogen bond, thus leading to a transition state that is not directly related to the proton transfer. Rather, it governs the interbase shift within the A · T pair switching the hydrogen‐bonded pattern and then separating the normal A · T pair from the mispairing valley on its potential energy surface. The latter comprises three mismatched base pairs, easily converted to each other because of lower barriers (≈1 kcal/mol) of the corresponding proton transfers. It is demonstrated that, in terms of the Gibbs free energy taken at room T = 298.15 K, the most stable mispair in such valley is predicted to be less stable by 9.7 ± 2 kcal/mol than the Watson–Crick pair, thus implying that the spontaneous point mutations of this type occur as infrequently as to be characterized by an equilibrium constant of 10^?6 to 10^?9. This estimate falls into the well‐known experimental range of mutation frequency per base pair. The structure of a so‐called “base flipping” of the A · T base pair, originated from a breaking of its N₃(T)‐H … N₁ (A) hydrogen bond, is also found and reported in the current work for the first time. The transition state A · T ${}_{\text{ts}}^{\text{WC?H}}$ , which governs the conversion of the Watson–Crick pair of adenine · thymine into the Hoogsteen one and is related to a breaking of the N₆(A)–H … O₄(T), is also obtained and its energetical and geometrical features are discussed. © 2003 Wiley Periodicals, Inc. Int J Quantum Chem, 2003