Free energy perturbation (FEP) is applied to the calculation of the enantioselectivity in binding of three peptide guest molecules to certain C-3-symmetric synthetic receptors. The calculations are able to reproduce the observed trends in enantioselection with errors less than or equal to 0.7 kcal/mol, and the agreement with experiment is the best with those guests which form stronger complexes. We find that the weakly bound guests sample more conformational space in the receptor complex than do the more strongly binding guests. These results indicate that obtaining the necessary converged ensemble averages is more challenging for the more weakly binding guests because their complexes are structurally more poorly defined. Our simulations also suggest that the high enantioselectivities observed with our receptors arise in large part from the ability of the preferred guest peptides to form, on average, a greater number of hydrogen bonds with the receptor.