Experimentally determined water/chloroform partition coefficients for three indole derivatives (3-methylindole, N-acetyltryptamine, and 3-(3’-indolyl)propionic acid N-methylamide), models of the amino acid tryptophan, are compared to free-energy differences calculated using molecular dynamics simulations. The effect of the choice of force field, the choice of pathway along which the free-energy change is calculated, the inclusion of free-energy contributions from constraints, and the treatment of long-range interactions on the agreement with the experimental data for this system are investigated with an eye to understanding the importance of the different aspects of the molecular model and computational procedure. It is demonstrated that, although the compounds are neutral and do not differ much in dipole moment or charge distribution, the incorporation of a reaction field to treat long-range electrostatic interactions is necessary to reproduce the experimentally observed trends. The implications of these findings for free-energy calculations in general and for the estimation of partition coefficients in particular are discussed.