Using Molecular Dynamics Free Energy Simulation to Compute Binding Affinities of DNA G-Quadruplex Ligands

We provide a practical guide for using molecular dynamics simulation to compute the binding affinity of small molecules in complex with G-quadruplex DNA. Such calculations have a number of applications, such as rescoring docking results and validating docked poses, to inform the discovery of G-quadruplex binders with high affinity and selectivity. This chapter describes two binding free energy protocols: the double decoupling method (DDM) and the potential of mean force method (PMF). We illustrate the application of the two methods using a recent case study of the binding of quindoline with the c-MYC G-quadruplex DNA. For this system, the two methods yield absolute binding free energies within ~2 kcal/mol of the experimental value. We discuss the advantages and disadvantages of these binding free energy methods.