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Protein-induced membrane disorder: a molecular dynamics study of melittin in a dipalmitoylphosphatidylcholine bilayer
1School of Chemistry, Tel Aviv University, Ramat Aviv, Tel Aviv 69978, Israel.
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.
Insights
Molecular dynamics simulations reveal melittin disrupts the lower phospholipid bilayer layer more than the upper layer, causing disorder and deformation. This asymmetry influences melittin-induced membrane lysis.
Area of Science:
- Biophysics
- Computational Biology
- Membrane Biophysics
Background:
- Melittin is a peptide toxin known to interact with and permeabilize cell membranes.
- Understanding melittin's interaction with lipid bilayers is crucial for elucidating its lytic mechanisms.
- Phospholipid bilayers, such as dipalmitoylphosphatidylcholine (DPPC), serve as model systems for cell membranes.
Purpose of the Study:
- To investigate the molecular dynamics of melittin embedded within a hydrated DPPC lipid bilayer.
- To analyze the asymmetric effects of melittin on the intracellular and extracellular layers of the bilayer.
- To explore the relationship between melittin's structure, membrane deformation, and potential lytic activity.
Main Methods:
- Performed a large-scale molecular dynamics simulation of a system comprising 72 DPPC molecules, a 26-amino acid melittin peptide, and over 3000 water molecules.
- Analyzed peptide orientation, phospholipid structural changes (deuterium order parameters, fractional free volume), and bilayer deformation.
- Examined the peptide's secondary structure and tilt angle relative to the membrane normal.
Main Results:
- Melittin induced greater disorder and structural deformation in the lower (intracellular) DPPC layer compared to the upper (extracellular) layer.
- The upper layer exhibited a tilt relative to the bilayer normal, while the lower layer showed increased fractional free volume and localized deformation.
- Melittin adopted a significant tilt (25 degrees) relative to the membrane normal, retaining a helical structure with an intrahelical bend.
Conclusions:
- The asymmetric interaction of melittin with the DPPC bilayer, likely due to its partial transmembrane orientation, contributes to its lytic effects.
- Local membrane deformation and water penetration in the vicinity of the peptide are key factors in melittin-induced membrane disruption.
- The observed peptide tilt and correlated lipid tilt in the upper layer suggest a mechanism for membrane perturbation.