Consensus Conformations of Dinucleoside Monophosphates Described with Well-Converged Molecular Dynamics Simulations

Dinucleoside monophosphates (DNMPs) have been described using various experimental approaches as flexible molecules which generate ensembles populating at least a small set of different conformations in solution. However, due to limitations of each approach in its ability to delineate the ensemble of conformations, an accurate and quantitative description of certain conformational features has not been performed for all DNMPs. Here, we apply a temperature replica-exchange molecular dynamics approach to fully and quickly converge conformational distributions of all RNA DNMPs immersed in the TIP3P water model using the AMBER ff14 force field. For a selection of DNMPs, the conformational ensembles were also generated when immersed in the OPC water model using alternative AMBER and CHARMM force fields. The OPC water model and other force field choices did not introduce new conformational classes but shifted the populations among existing conformations. Except for pyrimidine-pyrimidine dinucleosides, all other DNMPs populated four major conformations (which are defined in the main text and labeled A-form, Ladder, Inverted, and Sheared), in addition to an Extended form. Pyrimidine-pyrimidines did not generate the Sheared conformation. Distinguishing features and stabilizing factors of each conformation were identified and assessed based on the known experimental interpretations. The configuration of the glycosidic bond and the nonbonding interactions of hydrogen bond acceptors with the 2'-hydroxyl group were found to play determining roles in stabilizing particular conformations which could serve as a guide for potential force field modifications to improve the accuracy. Additionally, we computed stacking free energies based on the DNMP conformational distributions and found significant discrepancies with a previous study. Our investigation determined that the AMBER force field was incorrectly implemented in the previous study. In the future, this simulation approach can be used to quickly analyze the effects of new force field modifications in shifting the conformational populations of DNMPs, and can can be further applied to foresee such effects in larger RNA motifs including tetranucleotides and tetraloops.