Protein-Induced Membrane Disorder: A Molecular Dynamics Study of Melittin in a Dipalmitoylphosphatidylcholine Bilayer

Abstract

A molecular dynamics simulation of melittin in a hydrated dipalmitoylphosphatidylcholine (DPPC) bilayer was performed. The 19, 000-atom system included a 72-DPPC phospholipid bilayer, a 26-amino acid peptide, and more than 3000 water molecules. The N-terminus of the peptide was protonated and embedded in the membrane in a transbilayer orientation perpendicular to the surface. The simulation results show that the peptide affects the lower (intracellular) layer of the bilayer more strongly than the upper (extracellular) layer. 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 upper layer was less affected by the embedded peptide, except for an acquired tilt relative to the bilayer normal. The effect of melittin on the surrounding 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 transmembranal. Melittin's hydrophilic C-terminus anchors it at the extracellular interface, leaving the N-terminus "loose" in the lower layer of the membrane. In general, the simulation supports a role for local deformation and water penetration in melittin-induced lysis. As for the peptide, like other membrane-embedded polypeptides, melittin adopts a significant 25 degree tilt relative to the membrane normal. This tilt is correlated with a comparable tilt of the lipids in the upper membrane layer. The peptide itself retains an overall helical structure throughout the simulation (with the exception of the three N-terminal residues), adopting a 30 degree intrahelical bend angle.

Mechanism by which 2,2,2-trifluoroethanol/water mixtures stabilize secondary-structure formation in peptides: A molecular dynamics study

“…In line with the results of these previous studies we find that in TFE͞water MLT retains an almost linear conformation for at least 16 ns, whereas in water it rapidly bends in the proximity of residue 14. An extended conformation similar to what we observe has also been found in simulations of MLT in pure methanol (33), a membrane environment (32,39,40), and 1,1,1,3,3,3-hexafluoropropan-2-ol͞water mixtures (18).…”

A molecular dynamics study of the bee venom melittin in aqueous solution, in methanol, and inserted in a phospholipid bilayer

“…The TFE molecules are observed to aggregate around the peptide forming a matrix that partly excludes water, and thus favours intramolecular, local interactions such as backbone-backbone hydrogen-bonding, which is in line with experimental findings from NMR studies [45]. In a series of simulations the effect of melittin on lipid bilayers was investigated when adsorbed to the membrane surface [46][47][48][49], inserted as a single transmembrane helix in a bilayer [50], and as a tetrameric water pore in a lipid bilayer [51]. When absorbed on the bilayer surface melittin is found to have an effect on both leaflets of the membrane.…”

“…It causes thinning of the upper layer, which in turn favours water penetration through the lower layer [46]. Bachar and Becker [50] reported simulations of a single melittin molecule inserted in a dipalmitoylphosphatidylcholine (DPPC) bilayer in a transmembrane orientation and observed local disorder of the lipids in vicinity of the peptide. In the melittin pore simulation described by Lin and Baumga¨rtner [51], the individual helices in the tetrameric aggregate repelled each other due to their highly positively charged C-ter- Fig.…”

Protein folding in a reverse micelle environment: The role of confinement and dehydration

“…Early computational studies, including those of melittin 60,61 and alamethicin 62,63 in lipid bilayers, have provided insight into the role of a water-membrane interface in stabilizing the folded state of amphipathic helical proteins. By breaking the symmetry of the bulk solvent, peptides with a sequence that supports a folded state having a nonpolar face and a polar face have been known to associate with a membrane interface stabilizing the helical conformation both (1) at the interface (relative to bulk solution) and (2) in the helical conformation (relative to the disordered coil state).…”