Global minimum of the adenine center dot center dot center dot thymine base pair corresponds neither to Watson-Crick nor to Hoogsteen structures. Molecular dynamic/quenching/AMBER and ab initio beyond Hartree-Fock studies

Computational analysis of complete gas-phase potential energy and free ener gy surfaces of the adenine thymine base pair has been carried out. The stud y utilizes a combination of molecular dynamics simulations performed with C ornell et al. empirical force field and quenching technique. Twenty seven e nergy minima have been located at the potential energy surface of the adeni ne thymine base pair: nine of them are H-bonded structures, eight are T-sha ped dimers, and the remaining nine correspond to various stacked arrangemen ts. H-bonded structures are the most stable while stacked and T-shaped stru ctures are by more than 4 kcal/mol less stable than the global minimum, The global minimum and the first;two local minima utilize N-9-H and N-3 groups of adenine for the binding, i.e., the amino group N-6, and ring N-1 and N- 7 adenine positions are not involved in the base pairing. The most stable H -bonding patterns cannot occur in nucleic acids since the Ns position is bl ocked by the attached sugar ring. Hoogsteen and Watson-Crick type structure s (third and fourth local minima) are by about 3 kcal/mol less stable than the global minimum. Energetic preferences of the global minimum and first t wo local minima were confirmed by correlated MP2 ab initio calculations wit h 6-31G** and -6-311G(2d,p) basis sets. Relative population of various stru ctures (a quantity proportional to Delta G of base pair formation) was dete rmined by molecular dynamics simulations in the NVE microcanonical ensemble . Although the stability order of the global and first two local minima is unaffected by including the entropy contribution, the stability order of th e remaining structures is altered rather significantly in favor of stacked and T-shaped structures. The simulations further show that the population o f the global minimum is about 35% and it means that experimental gas-phase studies are likely to detect a vast number of mutually coexisting structure s.