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 {\hbox{C}}-4{\alpha } - {{\hbox{C}}-4}\prime - {{\hbox{N}}-9} - {{\hbox{N}}-{{10}}} and {{\hbox{N}}-9} - {{\hbox{N}}-{{10}}} - {{\hbox{C}}-5}\prime - {\hbox{C}}-5{\alpha } , 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.