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 N-3(T)-H...N-1 (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 (approximate to1 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 N-3(T)-H...N-1 (A) hydrogen bond, is also found and reported in the current work for the first time. The transition state A . T-WCdouble left right arrowH(ts), which governs the conversion of the Watson-Crick pair of adenine . thymine into the Hoogsteen one and is related to a breaking of the N-6(A)-H...O-4(T), is also obtained and its energetical and geometrical features are discussed. (C) 2003 Wiley Periodicals, Inc.