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.