Abstract Conformational energy calculations on Methionine-Enkephalin and on several of its analogues indicate that the calculated lowest energy conformation of the native enkephalin may not be the conformer which interacts at the opioid active site. Substitution at the end groups and various D and L-Alanine analogs were examined and a low energy conformation which differs from the native low energy conformer was found for the very active analog, [D-Ala2]-Met-Enkephalin-NH2. The stereopositions of side-chain functional groups are discussed and compared to the structure of morphine.