The flexible backbone of aminoethylglycine (aeg) PNA upon substitution becomes sterically constrained to ordain conformational pre-organization for preferential binding to DNA or RNA. The bulky gemdimethyl (gdm) substitution on carbons...
Peptide nucleic acids (PNAs) consist of an aminoethylglycine (aeg) backbone to which the nucleobases are linked through a tertiary amide group and bind to complementary DNA/RNA in a sequence-specific manner. The flexible aeg backbone has been the target for several chemical modifications of the PNA to improve its properties such as specificity, solubility, etc. PNA monomers exhibit a mixture of two rotamers (Z/E) arising from the restricted rotation around the tertiary amide N−CO bond. We have recently demonstrated that achiral gemdimethyl substitution at the α, β, and γ sites on the aeg backbone induces exclusive Z (α-gdm)-or E-rotamer (β-gdm) selectivity at the monomer level. It is now shown that γ/β-gdm-PNA:DNA parallel duplexes are more stable than the analogous antiparallel duplexes, while γ/β-gdm-PNA:RNA antiparallel duplexes are more stable than parallel duplexes. Furthermore, the γ/β-gdm-PNA:RNA duplexes are more stable than the γ/β-gdm-PNA:DNA duplexes. These results with γ/β-gdm-PNA are the reverse of those previously seen with α-gdm-PNA oligomers that stabilized antiparallel α-gdm-PNA:DNA duplexes compared to α-gdm-PNA:RNA duplexes. The stability of antiparallel/parallel PNA:DNA/RNA duplexes is correlated with the preference for Z/E-rotamer selectivity in α/β-gdm-PNA monomers, with Z-rotamers (α-gdm) leading to antiparallel duplexes and E-rotamers (β/γ-gdm) leading to parallel duplexes. The results highlight the role and importance of Z-and E-rotamers in controlling the structural preferences of PNA:DNA/RNA duplexes.
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