Molecular Modelling Methods to Quantitate Drug-DNA Interactions

We describe a molecular modelling method for calculating the binding affinity of ligands for DNA. Though theoretically applicable to any form of noncovalent interaction, we concentrate on the case of predicting the sequence selectivity of a minor-groove binding ligand. The method is based on performing molecular dynamics (MD) simulations on DNA sequences, with and without the ligand bound, and postprocessing the molecular dynamics trajectory data to obtain approximate free energies of binding. We discuss issues relating to the preparation of the structures for simulation, choices for the molecular dynamics simulation method itself, methods for evaluating the reliability and stability of the simulation data, and finally alternative approaches to postprocessing the data to extract approximate free energies of binding.