Factors involved in guanine/cytosine (G/C) selectivity of DNA-binding drugs: a molecular modelling study of ligand interactions with a tyrT DNA sequence

Abstract

Molecular modelling studies are reported on the interactions of two analogues of the bis(amidinium) drug berenil with an extended DNA sequence, the 60 base-pair sequence from the tyrT promoter. These analogues have the hydrogen bond-donating amidinium groups of this agent replaced by hydrogen bond-accepting carbonyl moieties. Since the amidinium functions facilitate binding of the parent drug to AT-rich sequences of DNA, one goal of this study has been to examine the potential for the modified analogues to interact with GC-rich regions in the minor groove of DNA. The molecular modelling strategy involves screw-type translation of the ligand molecules along the length of the duplex DNA sequence at 0.05 nm intervals and energy minimisation using an all-atom force-field. The contributions to the binding interaction are examined in terms of the van der Waals and electrostatic non-bonded energy components and the induced perturbation terms. It is found that conversion of one amidinium group to an amide function is insufficient to produce GC-binding selectivity, whereas conversion of both terminal groups does confer some selectivity for G · C base-pairs, although at the expense of reduced overall DNA binding affinity. The roles played by the various contributors to the binding energy and the factors that influence possible recognition of G · C base-pairs are analysed in detail.