Invisible RNA state dynamically couples distant motifs

Significance We recently showed, using NMR relaxation dispersion, that the HIV-1 transactivation response element (TAR) RNA forms a transient state (lifetime ∼45 μs and population ∼13%) through localized changes in base pairing within the apical loop. Here, we report a second transient TAR state that has longer lifetime (∼2 ms) and smaller population (∼0.4%) that simultaneously remodels the bulge and apical loop, which are separated by four Watson–Crick base pairs. This is accomplished by a global change in the register of bulge residues, which pair up with residues in the upper stem, causing reshuffling of base pairs that propagates to the apical loop and creation of three noncanonical base pairs. Thus, transient states provide a mechanism for dynamically coupling distant RNA motifs.