Global minimum of the adenine•••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 energy surfaces of the adenine thymine base pair has been carried out. The study utilizes a combination of molecular dynamics simulations performed with Cornell et al. empirical force field and quenching technique. Twenty seven energy minima have been located at the potential energy surface of the adenine thymine base pair: nine of them are H-bonded structures, eight are T-shaped dimers, and the remaining nine correspond to various stacked arrangements. H-bonded structures are the most stable while stacked and T-shaped structures 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 blocked by the attached sugar ring. Hoogsteen and Watson-Crick type structures (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 two local minima were confirmed by correlated MP2 ab initio calculations with 6-31G** and -6-311G(2d,p) basis sets. Relative population of various structures (a quantity proportional to Delta G of base pair formation) was determined 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 the remaining structures is altered rather significantly in favor of stacked and T-shaped structures. The simulations further show that the population of the global minimum is about 35% and it means that experimental gas-phase studies are likely to detect a vast number of mutually coexisting structures.