Anna Szabolcs

Base-modified oligodeoxynucleotides. I. effect of 5-alkyl, 5-(1-alkenyl) and 5-(1-alkynyl) substitution of the pyrimidines on duplex stability and hydrophobicity

Abstract Properties of oligodeoxynucleotides essential for the antisense effect can be favourably modified by substitution of the heterocyclic base moiety. This is shown here for duplex stability by 5 alkyl, 5-(1-alkenyl) and 5-(1-alkynyl) substitution of the pyrimidines in the self-complementary (dT-dA) 10 and (dC-dG) 6 oligomers as well as for the hydrophobic character of the (dT-dA) 10 series.

Poly(amino2dA-dT) Isomerizes into the Unusual X-DNA Double Helix at Physiological Conditions Inducing Z-DNA in Poly(dG-methyl5dC)

It is demonstrated that a two-state conformational isomerization is induced in the poly(amino2-dA-dT) duplex by submillimolar concentrations of divalent magnesium cations in low-salt aqueous solution. The isomerization is fast and has a low degree of cooperativity. The resulting conformer is the unusual X-DNA double helix originally observed with poly(dA-dT) at very high concentrations of CsF. Interestingly, the X form is induced in poly(amino2dA-dT) under the physiological conditions when poly(dG-methyl5dC) assumes Z-DNA. The same conditions of stabilization are presumably connected with the fact, observed in previous phosphorus NMR studies, that Z- and X-DNA have similar polydinucleotide backbone architectures. Results presented in this work permit to specify base pair exocyclic groups responsible for the radically different conformational variability of the synthetic DNA molecules containing alternating purine-pyrimidine sequences of GC or AT base pairs.

Conformational Isomerizations of Poly(dA-dT) Are Dramatically Influenced by a Substitution of a Minor Amount of Adenine by Purine or Amino2purine

We have synthesized poly(dA,dPu-dT) and poly(dA,n2dPu-dT) containing, respectively, 5.7% of purine and 7.4% of amino2purine in place of adenine to demonstrate that these apparently negligible perturbations of the primary structure have dramatic consequences for the polynucleotide conformational isomerizations. The replacement of adenine by amino2purine, preserving the number of hydrogen bonds between the complementary bases, has a stronger effect on the polynucleotide conformational isomerizations than the replacement with purine that is bound only by a single hydrogen bond to thymine. Nevertheless, poly(dA,dPu-dT) forms a more thermostable duplex than poly(dA,n2dPu-dT). Furthermore the few amino2purines in poly(dA,n2dPu-dT) inhibit its isomerization into X-DNA, stabilize but modify A-DNA and stabilize Z-DNA. Kinetics of the B-Z transition of poly(dA,n2dPu-dT) is fast to indicate that the amino groups in the double helix minor groove substantially decrease the kinetic barrier between B- and Z-DNA. On the other hand, the replacement of adenine by purine destabilizes both Z-DNA and A-DNA, and the destabilization of X-DNA is weaker than with amino2purine. A-form and B-form perhaps coexist in poly(dA,dPu-dT) at high concentrations of ethanol.

Interaction specificity of benzimidazol group compounds with AT-containing polynucleotides.

The interaction between polynucleotides: poly(dA)-poly(dT), poly(dA-dT), poly(am2dA-dT), and the AT-specific compounds of benzimidazol group has been studied. It is been shown that these compounds bind to poly(dA)-poly(dT) and poly(dA-dT) at low and high salt concentration in solution. Poly(am2dA-dT) interacts with AT-specific compounds only at low salt, where this polynucleotide is in a B-form, but not at high salt, when the polynucleotide converts to another conformation. Thus, the interaction specificity of the groove-binding ligands is influenced not only by the minor groove substituents, but the peculiarities of the secondary structure of polynucleotides.