The probability distribution of side-chain conformations in [Leu] and [Met]enkephalin determines the potency and selectivity to μ and δ opiate receptors

The structure of enkephalin, a small neuropeptide with five amino acids, has been simulated on computers using molecular dynamics. Such simulations exhibit a few stable conformations, which also have been identified experimentally. The simulations provide the possibility to perform cluster analysis in the space defined by potentially pharmacophoric measures such as dihedral angles, side‐chain orientation, etc. By analyzing the statistics of the resulting clusters, the probability distribution of the side‐chain conformations may be determined. These probabilities allow us to predict the selectivity of [Leu]enkephalin and [Met]enkephalin to the known μ‐ and δ‐type opiate receptors to which they bind as agonists. Other plausible consequences of these probability distributions are discussed in relation to the way in which they may influence the dynamics of the synapse. © 2003 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 71: 577–592, 2003