Journal
CHEMBIOCHEM
Volume 23, Issue 8, Pages -Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cbic.202100707
Keywords
bPNA; DANN; peptides; secondary structures; triplexes
Funding
- NIH [GM111995, 1R01GM143543-01]
- NSF [DMR 1802432]
- Center for RNA Biology at OSU
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This study investigates the impact of amino acid composition and backbone modification on DNA binding of bifacial peptide nucleic acid (bPNA). The results demonstrate the tunability of bPNA-DNA hybrid stability through bPNA backbone structural propensities and amino acid composition.
We report herein a study on the impact of bifacial peptide nucleic acid (bPNA) amino acid composition and backbone modification on DNA binding. A series of bPNA backbone variants with identical net charge were synthesized to display either 4 or 6 melamine (M) bases. These bases form thymine-melamine-thymine (TMT) base-triples, resulting in triplex hybrid stem structures with T-rich DNAs. Analyses of 6 M bPNA-DNA hybrids suggested that hybrid stability was linked to amino acid secondary structure propensities, prompting a more detailed study in shorter 4 M bPNAs. We synthesized 4 M bPNAs predisposed to adopt helical secondary structure via helix-turn nucleation in 7-residue bPNAs using double-click covalent stapling. Generally, hybrid stability improved upon stapling, but amino acid composition had a more significant effect. We also pursued an alternative strategy for bPNA structural preorganization by incorporation of residues with strong backbone amide conformational preferences such as 4R- and 4S-fluoroprolines. Notably, these derivatives exhibited an additional improvement in hybrid stability beyond both unsubstituted proline bPNA analogues and the helically patterned bPNAs. Overall, these findings demonstrate the tunability of bPNA-DNA hybrid stability through bPNA backbone structural propensities and amino acid composition.
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