Orientation Dependence of DNA Blunt-End Stacking Studied by Free-Energy Simulations

DNA blunt ends can associate mediated by stacking interactions between the terminal base pairs that form blunt ends. The blunt end association plays a role in DNA repair and recombination processes and can also be of importance for the design of DNA-based nano-materials. Its function depends on the sequence and on the geometric arrangement that leads to stable interaction. For a stacked state, the relative orientation (twisting) of the base pairs is important. Molecular dynamics and advanced sampling simulations were used to calculate free energy change associated with twist changes of the stacked blunt-end base pairs. The calculations reproduce blunt stacking arrangements found in crystal structures of DNA oligonucleotides as free energy minima. To elucidate the physical origin of the stabilization of certain angular arrangements, the interactions between backbone atoms in the blunt-end stack were switched off in additional free energy calculations. It allows us to decipher the contributions to stacking stabilization due to the nucleobases and the backbone and to analyze the sequence dependence of the angular stacking preferences. Good qualitative agreement was also found for the comparison with quantum mechanical calculations. The results may help in the design of novel DNA-based materials.