Are Waters around RNA More than Just a Solvent? – An Insight from Molecular Dynamics Simulations

Hydrating water molecules are believed to be an inherent part of the RNA structure and have a considerable impact on RNA conformation. However, the magnitude and mechanism of the interplay between water molecules and the RNA structure are still poorly understood. In principle, such hydration effects can be studied by molecular dynamics (MD) simulations. In our recent MD studies, we observed that the choice of water model has a visible impact on the predicted structure and structural dynamics of RNA and, in particular, has a larger effect than type, parametrization, and concentration of the ions. Furthermore, the water model effect is sequence dependent and modulates the sequence dependence of A-RNA helical parameters. Clearly, the sensitivity of A-RNA structural dynamics to the water model parametrization is a rather spurious effect that complicates MD studies of RNA molecules. These results nevertheless suggest that the sequence dependence of the A-RNA structure, usually attributed to base stacking, might be driven by the structural dynamics of specific hydration. Here, we present a systematic MD study that aimed to (i) clarify the atomistic mechanism of the water model sensitivity and (ii) discover whether and to what extent specific hydration modulates the A-RNA structural variability. We carried out an extended set of MD simulations of canonical A-RNA duplexes with TIP3P, TIP4P/2005, TIP5P, and SPC/E explicit water models and found that different water models provided a different extent of water bridging between 2′-OH groups across the minor groove, which in turn influences their distance and consequently also inclination, roll, and slide parameters. Minor groove hydration is also responsible for the sequence dependence of these helical parameters. Our simulations suggest that TIP5P is not optimal for RNA simulations.