Oostenbrink Chris, van Gunsteren Wilfred F
Laboratory of Physical Chemistry, Swiss Federal Institute of Technology-Zürich, ETH Hönggerberg, CH 8093 Zürich, Switzerland.
J Comput Chem. 2003 Nov 15;24(14):1730-9. doi: 10.1002/jcc.10304.
Relative free energies for a series of not too different compounds can be estimated accurately from a single simulation of an unphysical reference state that encompasses the characteristic molecular features of the compounds. Previously, this method has been applied to the calculation of free energies of solvation and of ligand binding for small molecules. In the present study we investigate the limits to the accuracy of the method by applying it to a realistic model of the binding of a set of rather large ligands to the protein factor Xa, a key protein in current efforts to design anticoagulation drugs. The evaluation of the binding free energies and conformations of nine derivatives of a biphenylamidino inhibitor leads to insights regarding the effect of the size, flexibility, and character of the unphysical part of the ligand in the reference state on the accuracy of the predicted binding free energies.
