Ligand Recognition in Viral RNA Necessitates Rare Conformational Transitions

Abstract

Ribonucleic acids (RNAs) are conformationally flexible molecules that fold into three-dimensional structures and play an important role in different cellular processes as well as in the development of many diseases. RNA has therefore become an important target for developing novel therapeutic approaches. The biophysical processes underlying RNA function are often associated with rare structural transitions that play a key role in ligand recognition. In this work, we probe these rarely occurring transitions using nonequilibrium simulations by characterizing the dissociation of a ligand molecule from an HIV-1 viral RNA element. Specifically, we observed base-flipping rare events that are coupled with ligand binding/unbinding and also provided mechanistic details underlying these transitions.

Conformational dynamics and energetics of viral RNA recognition by lab-evolved proteins

“…In this regard, RNA motifs from the HIV genome [26][27][28] serve as good model systems [29][30][31] to understand the viral RNA recognition mechanism by lab-evolved proteins. The HIV-1 trans-activation response element RNA (TAR; Fig.…”

Reaction Coordinate and Thermodynamics of Base Flipping in RNA

“…We also observed that the flipping of a single base caused local rearrangements in the neighboring bases which then resulted in global structural transitions in a stem-loop of the dsRNA. We suggest that the approaches described in this work are potentially applicable to other RNA/ligand systems, for example, conformational transitions coupled to binding of a ligand molecule in an RNA element from HIV-1, as reported in our previous work …”

“…We suggest that the approaches described in this work are potentially applicable to other RNA/ligand systems, for example, conformational transitions coupled to binding of a ligand molecule in an RNA element from HIV-1, as reported in our previous work. 67 ■ ASSOCIATED CONTENT * sı Supporting Information…”

Role of salt-bridging interactions in recognition of viral RNA by arginine-rich peptides

“…According to the protocol developed by Jensen et al (110), we used the exponential averaging of the Jarzynski's equality (111) to estimate the PMF along the reaction coordinate from work distributions obtained using SMD simulations (105,112). We have previously demonstrated the utility of this approach for studying RNA-ligand interactions (102). The exponential averaging expression is as follows:…”