Combined MD and NMR results display that 2×2 GG/GG internal loops in GGGC/GGGC observed in r(G4C2) exp prefer syn-anti/anti-syn and anti-syn/anti-syn conformational states. Furthermore, while the C/C mismatches prefer single hydrogen bond states, we observed that the neighboring base pairs in 2×2 CC/CC internal loops affect the loop dynamics. For example, it was seen that CCCG/CCCG displays a single conformational state while two states were dominating GCCC/GCCC. Altogether, this study provides unique structural data on low populated conformations observed in folded states of r(G4C2) exp and r(C4G2) exp , which can be utilized in structure-based drug design to specifically and effectively target 2×2 GG/GG and 2×2 CC/CC internal loops detected in C9orf72 transcripts.