Toward a consensus view of duplex RNA flexibility

Abstract

The structure and flexibility of the RNA duplex has been studied using extended molecular dynamics simulations on four diverse 18-mer oligonucleotides designed to contain many copies of the 10 unique dinucleotide steps in different sequence environments. Simulations were performed using the two most popular force fields for nucleic acids simulations (AMBER and CHARMM) in their latest versions, trying to arrive to a consensus picture of the RNA flexibility. Contrary to what was found for DNA duplex (DNA(2)), no clear convergence is found for the RNA duplex (RNA(2)), but one of the force field seems to agree better with experimental data. MD simulations performed with this force field were used to fully characterize, for the first time to our knowledge, the sequence-dependent elastic properties of RNA duplexes at different levels of resolutions. The flexibility pattern of RNA(2) shows similarities with DNA(2), but also surprising differences, which help us to understand the different biological functions of both molecules. A full mesoscopic model of RNA duplex at different resolution levels is derived to be used for genome-wide description of the flexibility of double-helical fragments of RNA.

Figure 1

Smoothed RMSD (in Å) from A-RNA fiber conformation (in gray) and average structure (in black) for RNA/Parmbsc0 (on the left) and CHARMM27 simulations (right) for the central 14-mer of the four RNA sequences.

Figure 2

Ensemble at different times of simulation (on the left) and final (on the right) structures of the four RNA sequences for Parmbsc0 (at the top) and CHARMM27 (at the bottom) simulations. In the case of CHARMM27 simulations, some fragments undergo irreversible nonhelical transition. (Insets) Detailed images of some of the major distortions.

Figure 3

Comparison of averaged interstrand hydrogen-bonding interactions for every basepair along sequences 1 (on the top) and 4 (at the bottom) and along the time of simulation for Parmbsc0 (on the left) and CHARMM27 trajectories (right) for RNA. (Blue means three standard Watson-Crick hydrogen bondings; orange stands for two of them; green means only one hydrogen interaction; and white, no standard interaction between one base and its complement.)

Figure 4

Average helical parameters for RNA for the 10 unique representative basepair steps for translational (shift, slide, and rise; in Å) and rotational (tilt, roll, and twist; in degrees) parameters. The CHARMM27 values were taken after removing open steps.

Figure 5

Stiffness constants (translational ones in kcal/mol·Å² and rotational ones in kcal/mol·deg²) for the 10 representative dinucleotide steps associated to the different deformation modes comparing DNA/Parmbsc0 (in blue), RNA/Parmbsc0 (in green with lines), RNA/CHARMM27 (in red triangles), and derived for analysis of x-ray structural data (in black diamonds) values. (Bottom) Summation of stiffness constants for translational helical parameters (left), and the same for rotational helical parameters (right).