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Molecular dynamics simulations of the biphalin molecule, (Tyr-D-Ala-Gly-Phe-NH)(2), and the active tetrapeptide hydrazide, Tyr-D-Ala-Gly-Phe-NH-NH(2) were performed to investigate the cause of the increased μ and δ receptor binding affinities of the former over the latter. The simulation results demonstrate that the acylation of the two equal tetrapeptide fragments of biphalin produces the constrained hydrazide bridges [Formula: see text] and [Formula: see text], which in turn increase the opportunity of conformations for binding to μ or δ receptors. Meanwhile, the connection of the two active tetrapeptide fragments of biphalin also results in the constrained side chain torsion angle χ(2) at one of the two residues Phe. This constrained side chain torsion angle not only significantly increases the δ receptor binding affinity but also makes most of the δ receptor binding conformations of biphalin bind to the δ receptor through the fragment containing the mentioned residue Phe.

The conformational stability of the extended antiparallel dimer structure of Met-enkephalin in water was analyzed by examining the hydration structure of enkephalin using molecular dynamics simulations. The result shows that, despite of the hydrophicility of the terminal atoms in the pentapeptide, the main contributor for the stability of the dimer in water is the four intermolecular hydrogen bonds between the Gly(2) and Phe(4) groups. The three-dimensional model of the delta-opioid pharmacophore for this dimer structure was also established. Such a model was demonstrated to match the delta-opioid pharmacophore query derived from the non-peptides SIOM, TAN-67, and OMI perfectly. This result thus strongly supports the assumption that the dimer structure of Met-enkephalin is a possible delta-receptor binding conformation.