Molecular dynamics simulations of RNA and noncanonical DNA molecules. Successes and troubles
Saturday, May 7, 2005 - 10:15am - 11:00am
Since 2000, we have carried out an extensive set of RNA simulations, with cumulative time scale at this moment above 2 microseconds and individual simulations expanded up to 100 ns, with 6 published and ca 5 in preparation papers. The aim of the project is MD analysis of distinct classes of RNA systems, including main rRNA non-Watson-Crick motifs. The studied systems include frameshifting pseudoknot, several RNA kissing complexes and related extended duplexes, wide range of ribosomal kink-turns, 5S rRNA Loop E and its complex with L25 protein, sarcin-ricin loop, hepatitis delta virus ribozyme and some other systems. The simulations appear to provide unique qualitative insights into the RNA dynamics, including role of tightly bound waters (residency times 1-25+ ns), unprecedented cation binding sites with up to 100% occupancy and frequent solute-bulk cation exchange, distinct mechanical properties of various classes of ribosomal RNA that can be related to the function, and others. In response to the recent observations of / transitions in B-DNA, we reanalyzed all our MD data. Since the RNA molecules have often a low resolution and there are many possible substates of backbone in RNA, the analysis is not always straightforward. Nevertheless, until now, we did not identify anything what could be considered as evident backbone pathology. If there are / switches, they are mostly reversible and often can be identified as being between two established RNA backbone conformations. Quality of backbone at the end of the simulations is comparable to the experimental data and there is no degradation of the structures in the course of the simulations. It is also notable that the nature of conformational variability in RNA allows to direct the research in a rather qualitative way, thus modest force field imbalances could often be tolerated. In addition, the simulations appear to very well reproduce many aspects of RNA molecules established by crystallography, including water-mediated dynamics of A-minor type I interaction (the most prominent RNA tertiary motif) in K-turns, correct prediction of topology of bulged out bases subsequently confirmed by crystallography, stability of specific backbone states such as S-turn, correct prediction of mutated structure of spinach chloroplast Loop E independently verified by NMR and others. We do not suggest that the force field is perfect but we can safely claim that it can be used very successfully to study many aspects of RNA structural dynamics. At the same time, we recently reported a large-scale failure of simulations to predict topology of d(GGGGTTTTGGGG)2 quadruplex loops, which halted all our advances in the G-DNA field. It appears to be accompanied by the same backbone / switch as noticed in ABC B-DNA simulations.