Even though MD calculations are predicting GCCC to have multiple different conformational states compared to CCCG, these structures display similar properties such as the loop residues to prefer anti orientations, to stack in helical axis, and to form at least a single hydrogen bond state. As a result, NMR might not be able to distinguish these individual states displaying relatively similar characteristics. Furthermore, it is also possible that the RNA force fields are still not be able to properly represent the 2×2 CC/CC loops, which can explain the differences observed between the NMR data and MD predictions. In many cases, it is challenging for experimental approaches to provide the in-depth details of small molecule-RNA interaction, which can be investigated with computational methods instead. This approach is especially useful when investigating highly dynamic RNA structures, which can prefer multiple different conformational states. Even though complexity of an RNA structure presents challenges, it also provides unique opportunities in drug design, where one can capitalize specific conformational states to enhance specificity and sensitivity. RNA motifs such as internal loops can transiently switch between different conformational states introducing localized dynamics within RNA as shown here in 2×2 GG/GG and 2×2 CC/CC internal loops.