AbstractA Monte Carlo method is given to compute the binding affinity of a ligand to a protein. The method involves extending configuration space by a discrete variable indicating whether the ligand is bound to the protein and a special Monte Carlo move, which allows transitions between the unbound and bound states. Provided that an accurate protein structure is given, that the protein–ligand binding site is known, and that an accurate chemical force field together with a continuum solvation model is used, this method provides a quantitative estimate of the free energy of binding. © 2004 Wiley Periodicals, Inc. J Comput Chem 26: 243–251, 2005