Molecular dynamics of potential rRNA binders: single-stranded nucleic acids and some analogues.

By hindering or "silencing" protein translation in vivo, antisense nucleic acid analogues that hybridize to bacterial rRNA could serve as a promising class of antibacterial compounds. Thus, we performed a comparative analysis of the dynamical properties of modified oligonucleotides based upon a sequence (5')r(UGUUACGACU)(3') that is complementary to bacterial ribosomal A-site RNA. In particular, 25 ns explicit solvent molecular dynamics simulations were computed for the following six single-stranded decamers: (1) the above RNA in unmodified form; (2) the 2'-O-methyl-modified RNA; (3) peptide nucleic acid (PNA) analogues of the above sequence, containing either (a) T or (b) U; and (4) two serine-substituted PNAs. Our results show that 2'-O-methylation attenuates RNA backbone dynamics, thereby preventing interconversion between stacked and unstacked conformations. The PNA analogue is rendered less flexible by replacing uracil with thymine; in addition, we found that derivatizing the PNA backbone with serine leads to enhanced base-stacking interactions. Consistent with known solubility properties of these classes of molecules, both RNAs exhibited greater localization of water molecules than did PNA. In terms of counterions, the initially helical conformation of the 2'-O-methyl RNA exhibits the highest Na(+) density among all the simulated decamers, while Na(+) build-up was most negligible for the neutral PNA systems. Further studies of the conformational and physicochemical properties of such modified single-stranded oligomers may facilitate better design of nucleic acid analogues, particularly those capable of serving as specific, high-affinity ribosomal A-site binders.