Molecular dynamics simulations predict a tilted orientation for the helical region of dynorphin A(1-17) in dimyristoylphosphatidylcholine bilayers

The structural properties of the endogenous opioid peptide dynorphin A(1-17 ) (DynA), a potential analgesic, were studied with molecular dynamics simul ations in dimyristoylphosphatidylcholine bilayers. Starting with the known NMR structure of the peptide in dodecylphosphocholine micelles, the N-termi nal helical segment of DynA (encompassing residues 1-10) was initially inse rted in the bilayer in a perpendicular orientation with respect to the memb rane plane. Parallel simulations were carried out from two starting structu res, systems A and B, that differ by 4 Angstrom in the vertical positioning of the peptide helix. The complex consisted of similar to 26,400 atoms (dy norphin + 86 lipids + similar to 5300 waters). After >2 ns of simulation, w hich included >1 ns of equilibration, the orientation of the helical segmen t of DynA had undergone a transition from parallel to tilted with respect t o the bilayer normal in both the A and B systems. When the helix axis achie ved a similar to 50 degrees angle with the bilayer normal, it remained stab le for the next >1 ns of simulation. The two simulations with different sta rting points converged to the same final structure, with the helix inserted in the bilayer throughout the simulations. Analysis shows that the tilted orientation adopted by the N-terminal helix is due to specific interactions of residues in the DynA sequence with phospholipid headgroups, water, and the hydrocarbon chains. Key elements are the "snorkel model"-type interacti ons of arginine side chains, the stabilization of the N-terminal hydrophobi c sequence in the lipid environment, and the specific interactions of the f irst residue, Tyr. Water penetration within the bilayer is facilitated by t he immersed DynA, but it is not uniform around the surface of the helix. Ma ny water molecules surround the arginine side chains, while water penetrati on near the helical surface formed by hydrophobic residues is negligible. A mechanism of receptor interaction is proposed for DynA, involving the tilt ed orientation observed from these simulations of the peptide in the lipid bilayer.