Free energies of binding of polychlorinated biphenyls to the estrogen receptor from a single simulation.
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., < k(B)T). 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.
Oostenbrink
Chris
C
Laboratory of Physical Chemistry, Swiss Federal Institute of Technology Zürich, Zürich, Switzerland.
van Gunsteren
Wilfred F
WF
D002244:Carbon / Q000378:metabolism; D003198:Computer Simulation; D008024:Ligands; D008958:Models, Molecular; D011078:Polychlorinated Biphenyls / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D011960:Receptors, Estrogen / Q000737:chemistry* / Q000378:metabolism*; D013816:Thermodynamics
D008024:Ligands; D011960:Receptors, Estrogen; D002244:Carbon; D011078:Polychlorinated Biphenyls