Threonine6-bradykinin: molecular dynamics simulations in a biphasic membrane mimetic

The natural peptide [Thr6]-bradykinin, Arg1-Pro2-Pro3-Gly4-Phe5-Thr6-Pro7-Phe8-Arg9, has been conformationally examined by molecular dynamics simulations using a two-phase box consisting of H2O and CCl4 to mimic the micellar environment utilized in the 1H-NMR studies. The different conformations generated from distance geometry calculations were refined with extensive molecular dynamics simulations. The resulting conformations provide additional structural insight into the differing biological activities of native bradykinin and [Thr6]-bradykinin, produced by the one conservative substitution Thr6 for Ser6. In addition, the simulations give some indication of the interaction of the peptide with the biphasic, hydrophilic/hydrophobic environment of the micelle. Such information is vital given the accumulating data indicating that the peptide first interacts with the membrane before the membrane-bound receptor. The structures of membrane-bound [Thr6]-bradykinin developed here provide experimental support for the interaction of residues 7 and 8 with the core of the membrane-bound receptor and the N-terminus and C-terminal arginine interacting with the extracellular portion of the receptor.