Deoxyribonucleic acid (DNA) not only stores genetic information but also emerged as a popular drug target. Modified nucleotides/nucleosides have been extensively studied in recent years wherein the sugar/nucleobase/phosphate-backbone has been altered. Several such molecules are FDA approved, capable of targeting nucleic acids and proteins. In this article, we modified negatively charged phosphate backbone to marshall's acid-based neutral backbone and analyzed the resultant structures by utilizing Gaussian accelerated molecular dynamics simulations (1 μs) in aqueous media at 150 mM salt concentration. We noted that the double-helical marshall's nucleic acid structure was partially denatured during the course of simulations, however, after using conformationally locked sugar, the marshall's nucleic acid (hereby called MNA) maintained the double-helical structure throughout the simulations. Despite the fact that MNA has a more extended backbone than the regular DNA, surprisingly, both showed similar helical rise (~3.4 Å) along with a comparable Watson-Crick hydrogen bond profile. The backbone difference was majorly compensated in terms of helical twist (~56° (MNA) and ~ 35° (control DNA)). Further, we examined a few MNA based ss-dinucleotides as intercalating ligands for a regular B-DNA. Quite strikingly, the ligands unwinded the DNA and showed intercalating properties with high DNA binding affinities. Hence, the use of small fragments of MNA based molecules in DNA targeted drug discovery is foreseen.
Keywords: Binding free energies; Intercalators; Marshall's nucleic acid; Molecular dynamics simulations; Nucleic acid analogues.
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