A molecular dynamics study on opioid activities of biphalin molecule.

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.