⁄ . This CV was used in our previous studies of DNA intercalation. RESULTS & DISCUSSION a) Free energy landscape of GAGA tetraloop in the presence of L-arginine and D-arginine. Although we used five collective variables (CV), we have chosen two of them, the stem distance and ermsd parameter, to discuss and understand the free energy landscape associated with the folding-unfolding equilibrium of GAAA tetraloop in the presence of L-arginine (Fig. ) and D-arginine (Fig. ). While stem distance measures the extent of unfolding, ermsd captures various native and non-native base pairing and stacking geometries. Based on the free energy values, as indicated by the color bar, we have identified three broad regions: folded state (stem distance < 1.8 nm and ermsd < 2.0 nm), elongated unfolded states (stem distance > 4.0 nm and ermsd > 2.0 nm), and the misfolded states (1.8≥ stem distance≤ 4.0 and ermsd > 2.0 nm) and denoted them by F, U, and M, respectively. The minimum free energy path connecting the folded state to the unfolded state through the misfolded state was calculated using MULE program and is indicated by the black dotted lines in the Figs. and. Also, to get a clear picture of the three states, the free energy profile relative to the unfolded state was plotted against stem distance in Fig. . Figure shows that GAAA is stable by -21.1 kcal/mol in the presence of D-arginine while its stability is only -12.2 kcal/mol in the presence of L-arginine. The free energy stability of the misfolded state is similar (between -17 -18.0 kcal/mol) in presence of either of stereoisomers. However, the minimum in presence of L-arginine is flatter compared that that around D-isomer. Note that, the definition of misfolded state is with respect to the structure in presence of D-arginine. In case of L-arginine, the misfolded state forms the global minimum. Therefore, we can say that in presence of L-arginine, GAAA tetraloop does not fold to the hairpin structure at all. This shows the effect of stereospecificity in the given RNA sequence, and further the evidence for chirality-driven tetraloop folding-unfolding equilibria which correlates with the hypothesis on chiral amino acid dependent RNA interactions related to the origin of life.