Molecular insights into the Stereospecificity of Arginine in RNA tetraloop folding

One of the possible hypotheses for the homochirality of amino acids in the context of the origin of life is that only a particular stereoisomer provides preferential stability to RNA folding by acting as a chemical chaperon. This study probes into the molecular understanding of such preferential stability for a small GAAA RNA tetraloop in the presence of chiral arginine amino acids using a combination of umbrella sampling and parallel bias metadynamics involving five collective variables to tackle the multi-dimensional free energy landscape for faster, better, and more efficient estimation with controlled sampling. Our results show that the free energetic stability of RNA differs significantly in the presence of D- and L- arginine, giving rise to different un-folding rates. Interestingly, the folding rates are not altered. We show that the origin of the chirality difference in RNA folding–unfolding dynamics is due to the differences in configurational diversity of RNA by adopting different unnatural conformations accompanied by different binding modes of D-arginine and L-arginine towards the given RNA motif.