Conformational studies of chiral d-Lys-PNA and achiral PNA system in binding with DNA or RNA through a molecular dynamics approach

• An MD study of a chiral PNA molecule in interaction with DNA and RNA was performed.
• We study duplex stability of chiral and achiral PNA targeting DNA and RNA molecules.
• Structural effect of chiral modification on PNA backbone influences DNA/RNA duplex.
• We give insights on the development of PNA able to discriminate DNA or RNA.

The growing interest in peptide nucleic acid (PNA) oligomers has led to the development of a very wide variety of PNA derivatives. Among others, the introduction of charged chiral groups on a PNA oligomer has proven effective in improving DNA binding ability, complexation direction and cellular uptake. In particular, the introduction of three adjacent chiral monomers based on d-Lys in the middle of the PNA sequence (d-Lys-PNA) has produced noteworthy results in modulating the directionality of the binding with the DNA complementary strand and in mismatch detection. Here, through a molecular dynamics approach, a comparative study has been carried out to investigate the structural properties that drive the interaction of the chiral d-Lys-PNA and the corresponding achiral PNA system with DNA as well as RNA complementary strands, starting from the crystal structure of d-Lys-PNA in complex with DNA. The results obtained complement experimental data and indicate that the binding with the RNA molecule, compared to DNA, is differently affected by the addition of three d-Lys groups on the PNA backbone, suggesting that this modification could be taken into account for the development of new PNA-based molecules able to discriminate between DNA and RNA.

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