Molecular Dynamics Study of the Hybridization between RNA and Modified Oligonucleotides

MicroRNAs (miRNAs) are attractive drug candidates for many diseases as they can modulate the expression of gene networks. Recently, we discovered that DNAs targeting microRNA-22-3p (miR-22-3p) hold the potential for treating obesity and related metabolic disorders (type 2 diabetes mellitus, hyperlipidemia, and nonalcoholic fatty liver disease (NAFLD)) by turning fat-storing white adipocytes into fat-burning adipocytes. In this work, we explored the effects of chemical modifications, including phosphorothioate (PS), locked nucleic acid (LNA), and peptide nucleic acid (PNA), on the structure and energy of DNA analogs by using molecular dynamics (MD) simulations. To achieve a reliable prediction of the hybridization free energy, the AMOEBA polarizable force field and the free energy perturbation technique were employed. The calculated hybridization free energies are generally compatible with previous experiments. For LNA and PNA, the enhanced duplex stability can be explained by the preorganization mechanism...