Gemdimethyl Peptide Nucleic Acids (α/β/γ-PNA): E/Z-Rotamers Influence the Selectivity in the Formation of Parallel/Antiparallel -PNA:DNA/RNA Duplexes.

Peptide nucleic acids (PNAs) consist of an aminoethylglycine () 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 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 backbone induces exclusive Z (α-)- or E-rotamer (β-) selectivity at the monomer level. It is now shown that γ/β--PNA:DNA parallel duplexes are more stable than the analogous antiparallel duplexes, while γ/β--PNA:RNA antiparallel duplexes are more stable than parallel duplexes. Furthermore, the γ/β--PNA:RNA duplexes are more stable than the γ/β--PNA:DNA duplexes. These results with γ/β--PNA are the reverse of those previously seen with α--PNA oligomers that stabilized α--PNA:DNA duplexes compared to α--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--PNA monomers, with Z-rotamers (α-) leading to antiparallel duplexes and E-rotamers (β/γ-) 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.