The nature of base stacking: a Monte Carlo study

o elucidate the physical origin of the preference of nucleic acid bases for stacking over hydrogen bonding in water, Monte Carlo simulations were performed starting from Watson-Crick structures of the adenine-thymine, adenine-uracil and guanine-cytosine base pairs, as well as from the Hoogsteen adenine-thymine base pair, in clusters comprising 400 and 800 water molecules. The simulations employed a newly implemented Metropolis Monte Carlo algorithm based on the extended cluster approach. All simulations reached stacked structures, confirming that such structures are preferred over the hydrogen-bonded Watson-Crick and Hoogsteen base pairs. The Monte Carlo simulations show the complete transition from hydrogen-bonded base pairs to stacked structures in the Monte Carlo framework. Analysis of the average energies shows that the preference of stacked over hydrogen-bonded structures is due to the increased water-base interaction in these structures. This is corroborated by the increased number of water-base hydrogen bonds in the stacked structures.