The potentials of mean force (PMF) for the association of purine, adenine, thymine, guanine, cytosine, and uracil in aqueous solution are investigated using ab initio MP2/6-31G(d-0.25) calculations (diffuse d-polarization functions were used) and Langevin dipoles solvation model. The entropy contributions to the free energies for stacking and hydrogen bonding are approximated using the linear relationship between binding enthalpies and entropies determined here from the available experimental data. This methodology is used to evaluate the dependence of PMF, and the gas-phase and solvation energies on the twist angle (Ω) in a number of undisplaced face-to-back stacking complexes. Further, we characterized the vertical association of the parallel (Ω ) 0°) and antiparallel (Ω ) 180°) stacked cytosine dimers. The results show large compensation between the gas-phase and solvation energetics and an overall preference of the bases in the undisplaced face-to-back stacked complexes for the twist angles near 30°. An important exception from this trend involves the GC and CG complexes, for which the largest stabilization occurs for the twist angle near 180°. In addition, free energies for the formation of 27 hydrogen-bonded base pairs were determined and compared with their stacking counterparts. The calculated standard free energies for the formation of stacked and hydrogen-bonded complexes at 298 K and neutral pH fell in a narrow region between 0.3 and -1.9 kcal/mol. Here, the hydrogen-bonded Watson-Crick guanine‚cytosine base pair was found to be the most stable of all studied complexes. In agreement with the previous experimental findings, complexes containing purine bases were calculated to be more stable than their pyrimidine-containing counterparts.

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 N9−H and N3 groups of adenine for the binding, i.e., the amino group N6, and ring N1 and N7 adenine positions are not involved in the base pairing. The most stable H-bonding patterns cannot occur in nucleic acids since the N9 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 ΔG 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.

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