Molecular dynamics reveals the stabilizing role of loop closing residues in kissing interactions: comparison between TAR-TAR* and TAR-aptamer

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Abstract
A RNA aptamer (R06) raised against the trans‐ activation responsive (TAR) element of HIV‐1 was previously shown to generate a loop–loop complex whose stability is strongly dependent on the selected G and A residues closing the aptamer loop. The rationally designed TAR* RNA hairpin with a loop sequence fully complementary to the TAR element, closed by U,A residues, also engages in a loop–loop association with TAR, but with a lower stability compared with the TAR–R06 complex. UV absorption monitored thermal denaturation showed that TAR–TAR*(GA), in which the U,A kissing residues were exchanged for G,A, is as stable as the selected TAR–R06 complex. Consequently, we used the TAR–TAR* structure deduced from NMR studies to model the TAR–R06 complex with either GA, CA or UA loop closing residues. The results of the molecular dynamics trajectories correlate well with the thermal denaturation experiments and show that the increased stability of the GA variant results from an optimized stacking of the bases at the stem–loop junction and from stable interbackbone hydrogen bonds.