A microscopic approach to the in vacuo energetics of the binding of a water molecule to the side chain of tryptophan, modeled by an indole molecule, is presented. Two binding sites have been studied, the most bound one, which corresponds to the conventional NH−OH2 hydrogen bond and a slightly less bound, so-called π-type hydrogen bond in which the hydrogen atoms interact with the π aromatic ring of indole. The structure of these two complexation sites as well as the potential energy surface has been obtained by a semiempirical model coupled with efficient procedures for the exploration of the surface. The H-bonded complex was observed in the supersonic expansion, and its binding energy (4.84 ± 0.23 kcal/mol) was measured using a laser two-color photofragmentation technique. The nonstandard H-bonded complex, not observed with indole, was observed with 1-methylindole, a substituted indole, in which the formation of the conventional bond is hindered. Its binding energy, measured with a similar accuracy (4.10...