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Institute for Advanced Simulations (IAS)

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The HIV-1 trans-activation responsive RNA (TAR) is located at the 5’-end of the viral transcripts. It forms a complex with the virally encoded Tat protein, which is crucial for HIV-1 replication. Upon Tat binding, TAR undergoes large conformational changes. How these conformational changes occur is still not fully clarified.

The challenges to understand the dynamics of TAR and its role in ligand recognition involve interplay of several internal motions characterized by time scaling ranging from pico to milliseconds. The insights from solution and solid-state NMR experiments are still not conclusive. Therefore, we propose to examine the conformational selection mechanism of TAR-ligand recognition by performing molecular dynamics simulations in the microsecond timescale using the latest release of the AMBER force field to reinterpret experimental results.

TARHIV-1 TAR: Sequence (A) and cartoon representation (B) of the structure from NMR studies. The apical loop, the bulge and the upper and lower stems are shown respectively in magenta, green, yellow and red color. (C) Representation of the angles involved in stems movement.

The structural changes of TAR are believed to be a promising feature to be exploited by knowledge-based drug development. The identification of TAR ligands preventing the formation of the TAR/Tat complex is a key strategy for therapeutic applications. Thus, we attempt to design new drugs, which can compete with the Tat in its binding sites and/or reinforce an inactive conformation of TAR. We use classical molecular dynamics together with non-equilibrium free energy techniques to estimate relative binding affinities of various drug candidates.
Our research is conducted in cooperation with the world-leading laboratories studying TAR, e.g. with the groups of Prof. G. Varani (University of Washington, USA) and Prof. O. Tabarrini (University of Perugia, Italy).