MOLECULAR-DYNAMICS SIMULATION OF MELITTIN IN A DIMYRISTOYLPHOSPHATIDYLCHOLINE BILAYER-MEMBRANE

Molecular dynamics trajectories of melittin in an explicit dimyristoyl phosphatidylcholine (DMPC) bilayer are generated to study the details of lipid-protein interactions at the microscopic lever. Melittin, a s mall amphipathic peptide round in bee venom, is known to have a pronou nced effect on the lysis of membranes. The peptide is initially set pa rallel to the membrane-solution interfacial region in an a-helical con formation with unprotonated N-terminus. Solid-state nuclear magnetic r esonance (NMR) and polarized attenuated total internal reflectance Fou rier transform infrared (PATIR-FTIR) properties of melittin are calcul ated from the trajectory to characterize the orientation of the peptid e relative to the bilayer. The residue Lys(7) located in the hydrophob ic moiety of the helix and residues Lys(23), Arg(24), Gln(25), and Gln (26) at the C-terminus hydrophilic form hydrogen bonds with water mole cules and with the ester carbonyl groups of the lipids, suggesting the ir important contribution to the stability of the helix in the bilayer . Lipid acyl chains are closely packed around melittin, contributing t o the stable association with the membrane. Calculated density profile s and order parameters of the lipid acyl chains averaged over the mole cular dynamics trajectory indicate that melittin has effects on both l ayers of the membrane. The presence of melittin in the upper layer cau ses a local thinning of the bilayer that favors the penetration of wat er through the lower layer. The energetic factors involved in the asso ciation of melittin at the membrane surface are characterized using an implicit mean-field model in which the membrane and the surrounding s olvent are represented as structureless continuum dielectric material. The results obtained by solving the Poisson-Bolztmann equation numeri cally are in qualitative agreement with the detailed dynamics. The inf luence of the protonation state of the N-terminus of melittin is exami ned. After 600 ps, the N-terminus of melittin is protonated and the tr ajectory is continued for 400 ps, which leads to an important penetrat ion of water molecules into the bilayer. These observations provide in sights into how melittin interacts with membranes and the mechanism by which it enhances their lysis.