Efficient in silico exploration of RNA interhelical conformations using Euler angles and WExplore.
Bottom Line: Our ensemble achieves similar agreement with experimental NMR data when compared with previous TAR computational studies, and is generated at a fraction of the computational cost.It clearly emerges from configuration space network analysis that the intermittent formation of the A22-U40 base pair acts as a reversible switch that enables sampling of interhelical conformations that would otherwise be topologically disallowed.We find that most previously determined ligand-bound structures are found in similar location in the network, and we use a sample-and-select approach to guide the construction of a set of novel conformations which can serve as the basis for future drug development efforts.
Affiliation: Department of Chemistry, University of Michigan, 930 N University, Ann Arbor, MI 48109, USA.Show MeSH
Mentions: HIV-1 TAR RNA plays a critical role in the infectivity of HIV; after it is transcribed by RNA Pol II, it binds the viral Tat and host Cyclin T1 proteins that are vital for promoting efficient transcription of the downstream HIV genome (14–16). As such, much work has focused on developing inhibitors of the interaction between TAR and Tat (17–23,70). In Figure 6, we map a set of known structures of TAR with inhibitors bound. For the four bound complexes shown at the top of Figure 6, there only exist a few states that are close to the bound structure, and they are not significantly populated as determined by the sampling in WExplore. Although this might suggest a binding mechanism of induced fit, an alternative explanation is that these conformations are significantly populated in the dynamics of TAR, but are simply not populated here due to insufficient sampling. Consistent with our discussion above, these four complexes have near-coaxial interhelical conformations (βh = 3.8°, 7.2°, 3.0° and 7.5°, for ADP-1, Neomycin B, 2L8H and KP-Z-41, respectively). Note that we are using a Euler distance of 20° to define the smallest regions in WExplore, so a distance of greater than 20° can be considered to be not sampled by our ensemble.
Affiliation: Department of Chemistry, University of Michigan, 930 N University, Ann Arbor, MI 48109, USA.