HIV-1 TAR RNA Spontaneously Undergoes Relevant Apo-to-Holo Conformational Transitions in Molecular Dynamics and Constrained Geometrical Simulations

Abstract

We report all-atom molecular dynamics and replica exchange molecular dynamics simulations on the unbound human immunodeficiency virus type-1 (HIV-1) transactivation responsive region (TAR) RNA structure and three TAR RNA structures in bound conformations of, in total, ∼250 ns length. We compare the extent of observed conformational sampling with that of the conceptually simpler and computationally much cheaper constrained geometrical simulation approach framework rigidity optimized dynamic algorithm (FRODA). Atomic fluctuations obtained by replica-exchange molecular dynamics (REMD) simulations agree quantitatively with those obtained by molecular dynamics (MD) and FRODA simulations for the unbound TAR structure. Regarding the stereochemical quality of the generated conformations, backbone torsion angles and puckering modes of the sugar-phosphate backbone were reproduced equally well by MD and REMD simulations, but further improvement is needed in the case of FRODA simulations. Essential dynamics analysis reveals that all three simulation approaches show a tendency to sample bound conformations when starting from the unbound TAR structure, with MD and REMD simulations being superior with respect to FRODA. These results are consistent with the experimental view that bound TAR RNA conformations are transiently sampled in the free ensemble, following a conformation selection model. The simulation-generated TAR RNA conformations have been successfully used as receptor structures for docking. This finding has important implications for RNA-ligand docking in that docking into an ensemble of simulation-generated RNA structures is shown to be a valuable means to cope with large apo-to-holo conformational transitions of the receptor structure.

Recognition of viral RNA stem–loops by the tandem double-stranded RNA binding domains of PKR

“…The TAR RNA hexaloop is highly dynamic (Jaeger and Tinoco 1993) and has been shown to adopt significantly different conformations, depending on its association with ligands including small molecules, peptides, proteins, and other nucleic acid molecules (Bardaro et al 2009;Fulle et al 2010). Concerted motions in TAR RNA have been suggested as the basis for access to bound state conformations (Al-Hashimi et al 2002).…”

Target Flexibility in RNA−Ligand Docking Modeled by Elastic Potential Grids

“…As the ligand had not been purposefully distorted with respect to its bound conformation in the preparation step, it may thus not come as a surprise that good starting structures for the subsequent energy minimization step were generated that way. 16 As already observed in the case of proteinÀligand complexes, 23 it is the type of motion that influences the docking success in the case of elastic potential grids more strongly than the magnitude of motion. While our approach does allow one to consider backbone and base motions simultaneously, limitations of the approach become obvious if base movements are predominantly governed by rotational flip motions or if nucleotide movements lead to an exchange of interaction types, for example, H-bond donor vs acceptor.…”

“…However, we have demonstrated recently that molecular dynamics and constrained geometric simulations showed a tendency to sample bound HIV-1 TAR RNA conformations even when started from the unbound TAR RNA structure. 16 Notably, structural deviations could be reduced by up to 2.3 Å rmsd when compared to deviations between experimental structures. Furthermore, the simulated TAR RNA conformations were used successfully as receptor structures for docking.…”

“…Furthermore, the simulated TAR RNA conformations were used successfully as receptor structures for docking. 16 With respect to the work presented here, receptor conformations generated by simulation techniques should thus provide attractive target conformations to which elastic potential grids generated from an apo conformation can be deformed to, without having to take the time to recompute the potential grids for each receptor conformation. In addition, our approach would also allow deforming grids to intermediate conformations in between the apo and a target structure as well as to conformations obtained from linear combinations of vectors of structural deviation between apo and multiple target structures.…”

“…16 Analogous to proteinÀligand docking, 17 three major classes of approaches are conceivable. 12 First, plasticity can be implicitly considered applying a soft-docking strategy with attenuated repulsive forces between target and ligand, but the range of possible movements that can be covered this way is rather limited.…”