Revealing conformational dynamics of 2′-O-methyl-RNA guanine modified G-quadruplex by replica exchange molecular dynamics

Abstract

Thrombin-binding DNA aptamer (TBA) can fold into an antiparallel unimolecular G-quadruplex (G4) structure. Different types of modifications lead to various effects on the structure and stability of the G4 structure. Previous study has shown that a modified TBA (mTBA) that 2′-deoxy guanine (dG) at positions 10 and 11 in the TBA sequence were replaced by 2′-O-methyl-RNA guanine (2′OMe-G) can't fold into a well-defined G4 structure. In order to investigate the detailed structural information and probe the instability factors, we successfully employed the replica exchange molecular dynamics (REMD) to characterize the large conformational variations of the mTBA and systemically describe the influences of the 2′OMe-G on the mTBA in terms of conformation variations and the probability distributions of Hoogsteen hydrogen bonds, dihedral, sugar pucker and glycosyl torsion angle. Replacing position 10 with the 2′OMe-G (2′OMe-G10) induced a strong destabilization of the aptamer, while the 2′OMe-G at position 11(2′OMe-G11) was less destabilizing. More importantly, the glycosyl torsion angle and sugar pucker of 2′OMe-G10 were the most critical destabilization factors. These results were in good agreement with the theoretical and experimental results. Moreover, the structure information can be used as guidelines for the further design of modifications on G4 structure.