Steered molecular dynamics simulations of cobra cytotoxin interaction with zwitterionic lipid bilayer: no penetration
O V Levtsova1, M Yu Antonov, D Yu Mordvintsev
1Department of Biophysics, Biological Faculty, M.V. Lomonosov Moscow State University, Moscow, Russia.
Abstract:
Cobra cytotoxins, small proteins of three-fingered toxin family, unspecifically damage membranes in different cells and artificial vesicles. However, the molecular mechanism of this damage is not yet completely understood. We used steered molecular dynamics simulations to study the interaction of cardiotoxin A3 from Naja atra cobra venom with hydrated 1-palmitoyl-2-oleoyl-1-sn-3-phosphatidylcholine (POPC) bilayer. The studied system included one cytotoxin molecule, 64 lipid molecules (32 molecules in each monolayer) and 2500 water molecules. It was found that the toxin interacted with zwitterionic bilayer formed by POPC. During first nanosecond of simulation the toxin molecule was oriented toward membrane surface by loops' basement including cytotoxin regions Cys14-Asn19 and Cys38-Ser46. This orientation was stable enough and was not changed during next 6 ns of simulation. The obtained data suggest that cytotoxin molecule cannot penetrate into membrane composed of zwitterionic lipids without some auxiliary interaction.
Insights
Cobra cytotoxins interact with cell membranes, but how they cause damage is unclear. Simulations show cardiotoxin A3 from Naja atra binds to POPC lipid bilayers via specific loops, suggesting it needs help to penetrate membranes.
Area of Science:
- Biochemistry
- Molecular Biology
- Toxicology
Background:
- Cobra cytotoxins, part of the three-finger toxin family, are known to damage cell membranes.
- The precise molecular mechanisms underlying this membrane damage remain incompletely understood.
Purpose of the Study:
- To investigate the interaction between Naja atra cardiotoxin A3 and a hydrated 1-palmitoyl-2-oleoyl-1-sn-3-phosphatidylcholine (POPC) lipid bilayer.
- To elucidate the molecular dynamics of this interaction using simulations.
Main Methods:
- Steered molecular dynamics (SMD) simulations were employed.
- The simulation system comprised one cardiotoxin A3 molecule, 64 POPC lipid molecules, and 2500 water molecules.
- The interaction was studied over a 7-nanosecond simulation period.
Main Results:
- Cardiotoxin A3 demonstrated interaction with the zwitterionic POPC bilayer.
- The toxin adopted a stable orientation towards the membrane surface within the first nanosecond, primarily through its loop regions (Cys14-Asn19 and Cys38-Ser46).
- This orientation remained consistent throughout the simulation.
Conclusions:
- The study suggests that cardiotoxin A3 does not spontaneously penetrate membranes composed of zwitterionic lipids like POPC.
- Additional interactions or factors may be required for cytotoxin membrane penetration.
