We present free energy calculations on the Michaelis complexes of the catalytic antibody 17E8 with two substrates, which differ only in their side chains. Replacing a -CH2-group with a -S-increases K-M by a factor of about 5-8. This corresponds to a free energy ''preference'' for the -CH2-ligand of about 0.9-1.3 kcal/mol. The calculations semiquantitatively reproduce the experimental free energies and show that the preference for a -CH2-over a -S- is mainly due to the more favorable solvation free energy in the unbound form of the molecule.