Structural dynamics of DNA mimic foldamers

Abstract

DNA mimic foldamers are helically folded aromatic oligoamides bearing negatively charged side chains that mimic the shape and charge distribution of double-stranded B-DNA. They have been shown to bind to some DNA-binding proteins better than DNA itself and thus have potential to interfere with DNA-protein interactions. Their structure has been previously characterized in detail by X-ray crystallography. We have now investigated their structural dynamics both computationally and experimentally. The force field parameters of the building blocks required for DNA mimicry were optimized and implemented in AMBER to perform molecular dynamics simulations of the foldamer helices. The position of the negatively charged side chains on the helix, the charge state of the side chains, and the presence of salt were systematically varied. The simulations revealed that the global flexibility parameters for twisting and bending of the foldamer helices are of similar magnitude to those of B-DNA, though distinct kinking events and motions are involved. A range of sequences were then prepared for experimental investigations using ¹H NMR, UV-vis absorption and circular dichroism spectroscopies. Measurements revealed that the foldamer helices are stable over a broad range of temperature, pH and salt conditions in aqueous solutions, but that they nevertheless undergo structural changes when conditions are modified. An assay was developed to quantitatively assess foldamer helix stability through the measurement of the rate of interconversion between right-handed and left-handed diastereomeric conformers. Unexpectedly, suppressing some negatively charged side chains had a destabilizing effect on the helix, suggesting a more complex role of the side chains than electrostatic repulsions.