Peptide nucleic acid (PNA) is a synthetic DNA analog with the phosphate backbone replaced by the N-(2-aminoethyl)-glycine units. Even though the PNA backbone resembles the neutral peptide backbone, the PNA is structurally similar to DNA or RNA. Thus, PNA oligomers, obeying the Watson-Crick base pairing rules, form stable duplexes and triplexes with DNA and RNA. Since PNA is a modified nucleic acid, it is used in many sequence-specific applications, such as antisense or antigene silencing of protein expression and diagnostics. One of the advantages of PNA is that the artificial backbone makes it resistant to enzymatic degradation.<br/><br/>Simulations of PNA-involving systems require proper force field parameters. We have modified the CHARMM and Amber force fields for PNA by optimizing the PNA backbone torsion parameters. The dihedral torsion potentials were optimized based on high-level quantum mechanical calculations. The optimized force fields improved the stability of microsecond molecular dynamics simulations performed for experimental structures of PNA duplexes and triplexes with DNA and RNA. The microsecond long simulations of these complexes also enabled the analysis of hydration and ion distributions.<br/><br/>Furthermore, we applied the updated PNA force field to simulations of thermal dynamics of biologically relevant PNA-RNA, RNA-RNA and PNA-PNA decamer duplexes. The analysis of hydrogen bonds and stacking as a function of temperature showed a two-state melting transition. Moreover, the melting plots reproduced the order of thermal stability from UV-monitored melting experiments, with PNA-PNA being the most and RNA-RNA the least stable. Simulations of unfolding show that all PNA-PNA bases melt concomitantly, whereas the RNA-RNA and PNA-RNA duplexes start to unfold from the termini. Also, the PNA-PNA duplex displays the highest activation energy for melting.

Improved force fields for the simulations of structural and thermal dynamics of peptide nucleic acid (PNA) complexes with natural nucleic acids

ACS Fall 2020 Virtual Meeting

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