Inclusion of methoxy groups inverts the thermodynamic stabilities of DNA–RNA hybrid duplexes: A molecular dynamics simulation study

• 2′-O-methyl modifications drive the conformation of hybrid duplexes towards A-like.
• Hydrophobicity of methyl groups inverses thermodynamic stability of hybrids upon modification.
• Structural changes in hybrid prone to 2′-O-methyl modification depend on the base composition.

Modified nucleic acids have found profound applications in nucleic acid based technologies such as antisense and antiviral therapies. Previous studies on chemically modified nucleic acids have suggested that modifications incorporated in furanose sugar especially at 2′-position attribute special properties to nucleic acids when compared to other modifications. 2′-O-methyl modification to deoxyribose sugars of DNA–RNA hybrids is one such modification that increases nucleic acid stability and has become an attractive class of compounds for potential antisense applications. It has been reported that modification of DNA strands with 2′-O-methyl group reverses the thermodynamic stability of DNA–RNA hybrid duplexes. Molecular dynamics simulations have been performed on two hybrid duplexes (DR and RD) which differ from each other and 2′-O-methyl modified counterparts to investigate the effect of 2′-O-methyl modification on their duplex stability. The results obtained suggest that the modification drives the conformations of both the hybrid duplexes towards A-RNA like conformation. The modified hybrid duplexes exhibit significantly contrasting dynamics and hydration patterns compared to respective parent duplexes. In line with the experimental results, the relative binding free energies suggest that the introduced modifications stabilize the less stable DR hybrid, but destabilize the more stable RD duplex. Binding free energy calculations suggest that the increased hydrophobicity is primarily responsible for the reversal of thermodynamic stability of hybrid duplexes. Free energy component analysis further provides insights into the stability of modified duplexes.

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