Amino Acids as RNA-Folding Chaperones: Single Molecule Experiments Reveal Chiral Sensitivity

Early RNA-based life may have relied on amino acids to promote correct folding in RNA molecules, i.e. to act as RNA-folding chaperones. Chiral specificity in this interaction could have driven evolutionary mechanisms to favor a single chirality of amino acid, which may explain the origin of amino acid homochirality. To probe how chirality determines an amino acid’s influence on RNA folding dynamics, we have performed single molecule spectroscopy on a ubiquitous RNA tertiary motif, the tetraloop-tetraloop receptor (TL-TLR). Our kinetic measurements show that TL-TLR folding is sensitive to many amino acids, but only one amino acid, arginine, is observed to have a chirally-specific effect. The kinetic and thermodynamic features of this chiral interaction are presented, and with the help of all-atom molecular dynamics simulations, we propose a mechanistic interpretation of these results based on nonspecific arginine-RNA interactions.