In order to investigate the relation between the conformation and the ability to modulate dopamine receptors, conformational free-energy calculations using an empirical potential (ECEPP/3) and hydration shell model were carried out on the tripeptide +H2-Pro-Leu-Gly-NH2 (PLG) and its analogues in which the Leu residue is replaced with Phe, Ahx (L-2-aminohexanoic acid), Ile, Abu and Ala residues in the unhydrated and hydrated states. PLG and two tripeptides possessing Phe and Ahx residues show dopamine receptor modulating activity, while the other tripeptides do not. Irrespective of activities, PLG and its analogues are found to have the high probabilities to form beta-bends of types II and I in the unhydrated state. However, in the hydrated state, the beta-bend probabilities of the PLG analogues decrease significantly compared with those in the unhydrated state. These results indicate that the beta-bend structure is a necessary factor for the PLG analogues to be active, but not a sufficient factor, and that the interactions of water molecules with the backbone may force the tripeptides to be more distorted or extended. The size and the orientation of the hydrophobic moiety of the second residue seem to be of consequence in eliciting the activity of the tripeptides.