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, i.e., the single strands adopt stable helical structures similar to those in the duplex. For PS, the S and R isomers (Sp and Rp) have preferences for C2'-endo and C3'-endo sugar puckering conformations, respectively, and therefore Sp is less stable than Rp in DNA/RNA hybrids. In addition, the solvation penalty of Rp accounts for its destabilization effect. PS-LNA is similar to LNA as the sugar puckering is dominated by the locked sugar ring. This work demonstrated that MD simulations with polarizable force fields are useful for the understanding and design of modified nucleic acids.