Insight into the intrinsic flexibility of the SL1 stem‐loop from genomic RNA of HIV‐1 as probed by molecular dynamics simulation

Abstract

The SL1 stem-loop is the dimerization initiation site for linking the two copies of the RNA forming the HIV-1 genome. The 26 nucleotides stem contains a defect consisting on a highly conserved G-rich 1-3 asymmetrical internal loop, which is a major site for nucleocapsid protein binding. Several NMR attempts were undertaken to determine the internal loop structure in the SL1 monomer. However, the RNA constructs used in the different studies were largely mutated, in particular with replacement of the nine nucleotides apical loop by a tetraloop, and divergent results were obtained ranging from a rigid structure to a particularly large flexibility. To investigate the reasons for such discrepancies, we used molecular dynamics simulation of the SL1 monomer to probe the effect of mutations on the conformational stability of the internal loop and of the whole stem. It is found that in the wild-type sequence, the internal loop displays conformational variability originating mainly from the nine nucleotides apical loop flexibility that causes large conformational fluctuations (without changing the average structure) in the 7 bp duplex linking the apical and internal loops. The large amplitude atomic motions in the duplex are transmitted to the internal loop in which they induce conformational changes characterized by a labile hydrogen bond network such as G5 successively H-bonded to A29 and G30. On the contrary, with a four nucleotides apical loop, conformational fluctuations in the duplex are reduced by a factor of 2 and are not sufficiently energizing for promoting changes in the internal loop structure at the time scale of the simulations.

An RNA Molecular Switch: Intrinsic Flexibility of 23S rRNA Helices 40 and 68 5′-UAA/5′-GAN Internal Loops Studied by Molecular Dynamics Methods

“…X-ray and NMR studies of RNAs can be complemented by molecular dynamics (MD), which provides dynamic data and additional insight into the structure. − For instance, MD simulations can characterize isolated RNA building blocks independent of their structural context. The simulations capture intrinsic stochastic fluctuations of geometries and reveal intrinsic elastic properties that are important for function. − In addition, simulations can disclose whether an RNA building block is entirely internally relaxed or is deformed due to its interactions with the surroundings.…”

“…13 X-ray and NMR studies of RNAs can be complemented by molecular dynamics (MD), which provides dynamic data and additional insight into the structure. [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] For instance, MD simulations can characterize isolated RNA building blocks independent of their structural context. The simulations capture intrinsic stochastic fluctuations of geometries and reveal intrinsic elastic properties that are important for function.…”

Flexibility of Short-Strand RNA in Aqueous Solution as Revealed by Molecular Dynamics Simulation: Are A-RNA and A´-RNA Distinct Conformational Structures?

“…More recent studies have covered longer timescales with stable simulations of solvated and neutralized systems. [37][38][39][40][41][42][43] Comparative studies of duplex RNA and DNA have revealed a striking contrast in structural flexibility. 44,45 Attention has been focused both through experiment and simulation 46 on the phenomenon of base pair opening and closing, which has been found to occur much more readily in RNA than in DNA.…”