INTERACTION OF AN AMPHIPHILIC PEPTIDE WITH A PHOSPHOLIPID-BILAYER SURFACE BY MOLECULAR-DYNAMICS SIMULATION STUDY

Corticotropin-releasing factor (CRF) is the principal neuroregulator o f adrenocorticotropic hormone (ACTH) secretion, Previous experiments h ave demonstrated that CRF binds avidly to the surface of single egg ph osphatidylcholine vesicles and its amphiphilic secondary structure mig ht play an important role in the function. In this study, the interact ion of the residues 13-41 in human CRF with the surface of a DOPC bila yer was investigated by molecular dynamics (MD) simulation in order to understand the role of the membrane surface in the formation of the a mphiphilic a helix as well as to determine the effects of the peptide on the lipid bilayer. The model used included 60 DOPC molecules, 1 hel ical peptide (CRF(13-41)) on the bilayer surface, and explicit waters of solvation in the lipid polar head group regions, together with cons tant-volume periodic boundary conditions in three dimensions. The MD s imulation was carried out for 510 ps. In addition, CRF(13-41), initial ly in a helical form, was simulated ill vacuo as a control. The result s indicate that while it was completely unstable in vacuo, the peptide helical form was generally maintained on the bilayer surface, but wit h distortions near the terminal ends. The peptide was confined to the bilayer headgroup/water region, similar to that reported from neutron diffraction measurement of tripeptides bound to the phosphatidylcholin e bilayer surface (Ref 1). The amphiphilicity of the peptide marched t hat of the bilayer headgroup environment, with the hydrophilic side or iented toward water and the hydrophobic side making contact with the b ilayer hydrocarbon core. These results support the hypothesis that the amphiphilic environment of a membrane surface is important in the ind uction of peptide amphiphilic alpha-helical secondary structure. Two m ajor effects of the peptide on the lipids were found: the first CH2 se gment in the lipid chains was significantly disordered and the lipid h eadgroup distribution was broadened towards the water region.