Free energies of binding of polychlorinated biphenyls to the estrogen receptor from a single simulation

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Abstract
Relative free energies of binding to the ligand‐binding domain of the estrogen receptor have been calculated for a series of 17 hydroxylated polychlorinated biphenyls. Because traditional thermodynamic integration or perturbation approaches are hardly feasible for these numbers of compounds, the one‐step perturbation approach is applied and is shown to yield accurate results based on only two 2‐ns molecular dynamics simulations of an unphysical, judiciously chosen, reference state. The mean absolute difference between the calculated and experimental binding free energies for the 17 compounds is 3.4 kJ/mol, which illustrates the accuracy of the GROMOS biomolecular force field used. Excluding the three largest ligands from the comparison reduces the deviation to 2.0 kJ/mol (i.e., < kBT). Apart from the relative free energy, structural information about the binding mode and binding orientation for every compound can also be extracted from the simulation, showing that a ligand bound to its receptor cannot be represented by a single conformation, but it samples an ensemble of different orientations. Proteins 2004;54:000–000.