Zusammenfassung
HIV-1 TAR RNA is a two-helix bulge motif that plays
a critical role in HIV viral replication and is an important
drug target. However, efforts at designing TAR
inhibitors have been challenged by its high degree
of structural flexibility, which includes slow largeamplitude
reorientations of its helices with respect
to one another. Here, we use the recently introduced
algorithm WExplore in combination with Euler angles
to achieve unprecedented sampling of the TAR
conformational ensemble. 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. Collectively, our findings demonstrate the
utility of WExplore in combination with suitable order
parameters as a method for exploring RNA conformational
space.
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