Correlated Internal Motions in Left-Handed DNA Double Helices: Z-B Transition Driven by Drug Binding

Abstract

From molecular model building and fiber diffraction studies, it was earlier shown¹ that Z-DNA really represents a family of left-handed zig-zag helices (LZ helices for short). LZ1 and LZ2 helices were designated as two extremes. Although these two types of helices are different in overall topology, they share the following common properties: (i) a dinucleotide repeat with guanine in (C3’-endo, syn) conformation while cytosine in (C2’-endo, anti) conformation, (ii) intrastrand stacking in the GpC sequence and interstrand stacking in the CpG sequence, (iii) oxygen atoms in the successive sugar residues in a given strand pointing in the opposite directions while the oxygen atoms of the sugars across a base-pair pointing in the same direction. The essential difference between the LZ1 & LZ2 helices is in the P-O torsions of the GpC fragment. In the LZ1 helix the P-O torsions in the GpC fragment are g⁻,t while in the LZ2 helix they are g⁺,g⁺. Thus, by correlated internal motions around the P-O bonds in the GpC fragment it is possible to switch from LZ1 to LZ2 helix (and vice-versa) without ever disturbing the base-pairing. This (LZ1 to LZ2) is a local order to order transition achieved by correlated internal motions and hence there is little or no energy barrier. However,the effect of correlated internal motions in the LZ helices can be more dramatic than that. In this paper, we demonstrate that such motions in the LZ helices can also generate breathing modes resulting in the sequence specific drug intercalation.

Publication No. 4 from National Foundation for Cancer Research State University of New York at Albany