Protein-induced membrane disorder: A molecular dynamics study of melittin in a dipalmitoylphosphatidylcholine bilayer

A molecular dynamics simulation of melittin in a hydrated dipalmitoylphosph atidylcholine (DPPC) bilayer was performed. The 19,000-atom system included a 72-DPPC phospholipid bilayer, a 26-amino acid peptide, and more than 300 0 water: molecules, The N-terminus of the peptide was protonated and embedd ed in the membrane in a transbilayer orientation perpendicular to the surfa ce, The simulation results show that the peptide affects the lower (intrace llular) layer of the bilayer more strongly than the upper (extracellular) l ayer. The simulation results can be interpreted as indicating an increased level of disorder and structural deformation for lower-layer phospholipids: in the immediate vicinity of the peptide. This conclusion is supported by the calculated deuterium order parameters, the:observed deformation at the intracellular interface, and an increase in fractional free volume. The upp er layer was less affected;by the embedded peptide, except for an acquired tilt relative to the bilayer normal. The effect of melittin on the surround ing membrane is localized to its immediate vicinity, and its asymmetry with respect to the two layers may result from the fact that it is not fully tr ansmembranal, Melittin's hydrophilic C-terminus anchors it at the extracell ular interface, leaving the N-terminus "loose" in the lower layer of the me mbrane. In general, the simulation supports a role for local deformation an d water penetration in melittin-induced lysis, As for the peptide, like oth er membrane-embedded polypeptides, melittin adopts a significant 25 degrees tilt relative to the membrane normal. This tilt is correlated:with a compa rable tilt of the lipids in the upper membrane layer, The peptide itself re tains an overall helical structure throughout the simulation (with the exce ption of the three N-terminal residues), adopting a 30 degrees intrahelical bend angle.