Understanding RNA Flexibility Using Explicit Solvent Simulations: The Ribosomal and Group I Intron Reverse Kink-Turn Motifs

Abstract

Reverse kink-turn is a recurrent elbow-like RNA building block occurring in the ribosome and in the group I intron. Its sequence signature almost matches that of the conventional kink-turn. However, the reverse and conventional kink-turns have opposite directions of bending. The reverse kink-turn lacks basically any tertiary interaction between its stems. We report unrestrained, explicit solvent molecular dynamics simulations of ribosomal and intron reverse kink-turns (54 simulations with 7.4 μs of data in total) with different variants (ff94, ff99, ff99bsc0, ff99χOL, and ff99bsc0χOL) of the Cornell et al. force field. We test several ion conditions and two water models. The simulations characterize the directional intrinsic flexibility of reverse kink-turns pertinent to their folded functional geometries. The reverse kink-turns are the most flexible RNA motifs studied so far by explicit solvent simulations which are capable at the present simulation time scale to spontaneously and reversibly sample a wide range of geometries from tightly kinked ones through flexible intermediates up to extended, unkinked structures. A possible biochemical role of the flexibility is discussed. Among the tested force fields, the latest χOL variant is essential to obtaining stable trajectories while all force field versions lacking the χ correction are prone to a swift degradation toward senseless ladder-like structures of stems, characterized by high-anti glycosidic torsions. The type of explicit water model affects the simulations considerably more than concentration and the type of ions.

Ligand-mediated and tertiary interactions cooperatively stabilize the P1 region in the guanine-sensing riboswitch

“…Accordingly, the comparison of the average conformation over the last 50 ns of MD simulations with the crystal structure shows only small overall structural deviations (S4 Fig). The ff99 force field used here has been reported to lead to irreversible transitions to unexpectedly open and under-twisted RNA structures resembling a ladder due to anti to high- anti shifts of the χ dihedral [43,45–47]. However, visual inspection of our MD trajectories neither revealed the formation of such ladder-like structures for Gsw apt nor for Gsw loop (S4 Fig).…”

Molecular dynamics simulations of G-DNA and perspectives on the simulation of nucleic acid structures

“…We are not aware of any report proving markedly different nucleic acid structural dynamics with net-neutral and excess salt conditions, however there are issues with specific ion parameters and lack of their mutual balance [153]. We have explicitly compared simulations with different ion conditions for several classes of nucleic acids and the results are so far similar [154,155]. Experimentally detected ion binding sites are usually well reproduced; cf., e.g.…”

“…Recent RNA simulations revealed that the simulation results are affected by the water model to a certain extent and there is a coupling between the solute force field and water model properties [154]. We presently test if the water model might have some effect on G-DNA simulations.…”

Isosteric and Nonisosteric Base Pairs in RNA Motifs: Molecular Dynamics and Bioinformatics Study of the Sarcin–Ricin Internal Loop

“…They confirmed that the χ OL3 correction is essential to achieve stable RNA simulations. 36,63,64,66 Without applying this correction, the force field imbalances would disturb the simulated structures before we could get enough data to assess the base substitutions. More details can be found in Supporting Information.…”