Book of Abstracts: Albany 2005
Non-empirical Studies of the DNA Rare Base Pairs: The Molecular Mechanism of the Spontaneous Substitution Mutations Conditioned by Tautomerism of Bases
Gas-phase gradient optimization of the DNA rare base pairs containing the lactim forms of guanine (G*) and thymine (T*) as well as the imino forms of cytosine (C*) and adenine (A*) tautomers were carried out using the Hartree-Fock (HF), Density Functional theory (DFT) and the second-order Moller-Plesset perturbation (MP2) methods at the 6-31G(d,p) basis set. It is shown that full geometry optimization at the MP2 level leads to an intrinsically nonplanar propeller-twisted and buckled geometry of the G*-T and G-T* base pairs. The nonplanarity of these pairs is caused by the pyramidalization of the amino nitrogen atoms, which is underestimated by the HF and DFT methods. Hessian calculations at the MP2/6-31G(d,p) level were performed on the optimized geometry of the rare base pairs in order to verify a nature of the stationary point obtained. Calculations of the force constant matrix for the MP2/6-31G(d,p) wavefunctions were carried out by the numerical finite difference method. Inspection of the harmonic frequencies for normal vibrations of nonplanar rare base pair shows that their structures posses only real vibrational wavenumbers. This confirms that the optimized nonplanar structure represents a local minimum on the MP2/6-31G(d,p) potential energy surfaces of the rare base pair. The comparison of the formation energies for the rare base pairs shows the energetical preference of the G*-T and A-C* base pairs as compared with the G-T* and A*-C ones, respectively. The MP2 calculations showed that the stabilization energies of the G-T* and A*-C base pairs describing the interaction between monomers are essentially larger than those of the G*-T and A-C* ones, respectively. The obtained data directly show that the calculated interaction energies of bases in the rare base pairs are insufficient in order to characterize the relative ease or difficulty of incorporating base pairs into a double helix. It was detected that the stability of the G-T* base pair is much larger than that of the canonical Watson-Crick G-C base pair which is considered at present as largest among all studied base pairs. Analysis of the decompositions for molecular HF interaction energies by Morokuma-Kitaura and the Reduced Variational Space methods showed that the nature of larger stability of the G-T* and A*-C base pairs as compared to the G*-T and A-C* ones, respectively is due to the electrostatic interactions by the 60-65% and the polarization and charge transfer interactions by 35-40%. The correlation interaction makes noticeably larger contribution to the stability of the G*-T and A-C* base pairs than to that of the G-T* and A*-C ones. Therefore the larger stability of the G-T* and A*-C base pairs is not related to the correlation interaction. According to the energetical point of view, the formation of the G*-T and A-C* base pairs must leads to the spontaneous mutations more often by comparison with the G-T* and A*-C ones, respectively. Analysis of the obtained results show that in the case of lactam-lactim and amino-imino tautomerism the replication errors mostly lead to the transition from G-C to A-T, whereas the insertion errors to the transition from A-T to G-C.
Victor I. Danilov1*
1Institute of Molecular Biology and Genetics