Large-Scale Analysis of 48 DNA and 48 RNA Tetranucleotides Studied by 1 μs Explicit-Solvent Molecular Dynamics Simulations.

An understanding of how the conformational behavior of single-stranded DNAs and RNAs depend on sequence is likely to be important for attempts to rationalize the thermodynamics of nucleic acid folding. In an attempt to further our understanding of such sequence dependences, we report here the results of 192 (1 μs) explicit-solvent molecular dynamics (MD) simulations of 48 DNA and 48 RNA tetranucleotide sequences performed using recently reported modifications to the AMBER force field. Each tetranucleotide was simulated starting from two different conformations, a fully natively stacked and a completely unstacked conformation, and populations of the various possible base stacking arrangements were analyzed. The simulations indicate that, for both DNA and RNA, the populations of fully natively stacked conformations increase linearly with increasing numbers of purines in the sequence, while the conformational entropies, computed by two complementary methods, decrease. Despite the comparatively short simulation times, the computed free energies of stacking of the 16 possible combinations of bases in the middle of the sequences are found to be in good correspondence with values reported recently from simulations of dinucleoside monophosphates using the same force field. Finally, consistent with recent reports from other groups, non-native stacking interactions, i.e., between bases that are not adjacent in sequence, are shown to be a recurring feature of the simulations; in particular, stacking interactions of bases in a i:i+2 relationship are shown to occur significantly more frequently when the intervening base is a pyrimidine. Given that the high prevalence of non-native stacking interactions is thought to be unrealistic, it appears that further parametrization work will be required before accurate conformational descriptions of single-stranded nucleic acids can be obtained with current force fields.