Chiral peptide nucleic acids (PNAs): Helix handedness and DNA recognition

Peptide Nucleic Acids (PNAs) are DNA mimics in which the deoxyribose phosph ate backbone has been replaced by a pseudo-peptide skeleton composed of N-( 2-aminoethyl)glycine units; they bind to complementary DNA strands with hig h affinity and selectivity. In order to study the effect of stereogenic cen ters within the backbone on PNA preorganization and DNA binding properties, chiral PNA decamers were synthesized which contained thymine monomers deri ved from L-Leu and D- or L-Lys inserted either at C-terminus and/or in the middle of an achiral PNA strand. PNAs containing three chiral thymine monom ers derived from L-Leu, D- or L-Lys, L-Asp, or D-Glu were also synthesized. CD spectral analyses showed that a charged chiral monomer inserted in the middle of the strand is able to induce a strong preference in the helix han dedness of a PNA-PNA duplex. The effect is increased by the presence of thr ee chiral charged monomers. The L-Lys- and L-Asp-PNAs induced a preference for the left-handed and the D-Lys and D-Glu-PNAs for the right-handed confo rmation. As expected, the PNA-DNA duplexes are dominated by the DNA strand and thus are right-handed with both D- and L-PNAs. However, the D-PNAs, bei ng inherently right-handed, lead to more stable PNA-DNA duplexes than the L -PNAs. The lysine-based PNAs form more stable complexes with the DNA at low ionic strength, due to the electrostatic interactions between the charged lysine side chain and DNA.