The origin of spontaneous point mutations in DNA via Löwdin mechanism of proton tunneling in DNA base pairs: Cure with covalent base pairing*

The key aim of the present work is twofold. On the one hand, we propose a novel model of the tautomerization of the A⋅T base pair leading to its mismatches and supporting thus the Lowdin mechanism of the proton transfers taking place within the valley formed by its mispairs. Its specific novelty is actually in that the existing barrier of ca. 23 kcal/mol is not directly related to the proton transfer. Rather, it governs a shift of the bases within the Watson–Crick A⋅T base pair relative to each other and separates it from the valley in its potential energy surface where the mispairing occurs quite easily due to lower barriers of the proton transfers therein. On the other hand, aiming to cure the DNA double helix of generating hydrogen-bonded mispairs, which lead to the spontaneous point mutations in the genetic alphabet, by inserting covalent base pairs into the DNA architecture, we subject the covalent bond base pair designed recently by Gao and Orgel (Proc Natl Acad Sci USA 1999, 96, 14837) to the high-level performance computational study. Its three tautomeric forms are found and it is shown that the most stable one is characterized by the amide-type hydrogen bond. The comparison of the properties such as rotational constants, dipole moment, polarizability, and quadrupole moment is carried out for the Gao–Orgel covalent base pair and the canonical A⋅T one. We demonstrate that the former one can be easily inserted into the double helix DNA without any significant perturbations of the double helix architecture. © 2002 Wiley Periodicals, Inc. Int J Quantum Chem, 2002