Key result
MEL stabilizes base-flipped UU mismatches in CUG-repeat RNA while larger DAP fails to bind.
Why the study?
A fundamental understanding of binding interactions between RNA and small molecules and their complex structures is needed to inform the design of new targeting agents.
Computational modeling supports the feasibility of uracil base flipping in CUG-repeat RNA when bound to small molecule ligands, which may inform the design of new targeting agents for myotonic dystrophy type 1.
May inform ligand design for CUG-repeat RNA in myotonic dystrophy type 1; hypothesis-generating and requires experimental validation before any clinical consideration.
Small molecules can be used to target RNAs that mediate disease. A fundamental understanding of binding interactions between RNA and small molecules and the structure of their complexes will further inform the design of new targeting agents. Two small molecule ligands were investigated for their ability to recognize the expanded CUG repeat sequence in RNA, the causative agent of myotonic dystrophy type 1. We report the use of molecular dynamics simulations to explore small molecule–RNA complexes and the finding of a stabilized base flipped conformation at UU mismatches. The results of this computational study support experimental observations and suggest that base flipping is feasible for CUG-repeat RNA.
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Hagler et al. (2020) studied Myotonic dystrophy type 1 (DM1) - RNA target. MEL and DAP was evaluated on Binding stability and base flipping in RNA-small molecule complexes. Molecular dynamics simulations showed that MEL stabilizes a base-flipped conformation at UU mismatches in CUG-repeat RNA, while DAP does not bind effectively due to its larger size.
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