Molecular dynamics simulations of a stretch-activated channel inhibitor GsMTx4 with lipid membranes: two binding modes and effects of lipid structure.
Our recent molecular dynamics simulation study of hanatoxin 1 (HaTx1), a gating modifier that binds to the voltage sensor of K(+) channels, has shown that HaTx1 has the ability to interact with carbonyl oxygen atoms of both leaflets of the lipid bilayer membrane and to be located at a deep position within the membrane. Here we performed a similar study of GsMTx4, a stretch-activated channels inhibitor, belonging to the same peptide family as HaTx1. Both toxins have an ellipsoidal shape, a belt of positively charged residues around the periphery, and a hydrophobic protrusion. Results show that, like HaTx1, GsMTx4 can interact with the membrane in two different ways. When all the positively charged residues interact with the outer leaflet lipid, GsMTx4 can assume a shallow binding mode. On the other hand, when the electrostatic interaction brings the positively charged groups of K-8 and K-28 into the vicinity of the carbonyl oxygen atoms of the inner leaflet lipids, the system exhibits a deep binding mode. This deep mode is accompanied by local membrane thinning. For both HaTx1 and GsMTx4, our mean force measurement analyses show that the deep binding mode is energetically favored over the shallow mode when a DPPC (dipalmitoyl-phosphatidylcholine) membrane is used at 310 K. In contrast, when a POPC (palmitooleoyl-phosphatidylcholine) membrane is used at 310 K, the two binding modes exhibited similar stability for both toxins. Similar analyses with DPPC membrane at 330 K led to an intermediary result between the above two results. Therefore, the structure of the lipid acyl chains appears to influence the location and the dynamics of the toxins within biological membranes. We also compared the behavior of an arginine and a lysine residue within the membrane. This is of interest because the arginine residue interaction with the lipid carbonyl oxygen atoms mediates the deep binding mode for HaTx1, whereas the lysine residue plays that role for GsMTx4. The arginine residue generally shows smoother dynamics near the lipid carbonyl oxygen atoms than the lysine residue. This difference between arginine and lysine may partly account for the functional diversity of the members of the toxin family.
Nishizawa
Manami
M
Department of Biochemistry, Teikyo University School of Medicine, Kaga, Itabashi, Tokyo 173-8605, Japan.
Nishizawa
Kazuhisa
K
D003198:Computer Simulation; D004548:Elasticity; D036341:Intercellular Signaling Peptides and Proteins; D015640:Ion Channel Gating; D008051:Lipid Bilayers / Q000737:chemistry*; D008560:Membrane Fluidity; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D010455:Peptides / Q000737:chemistry*; D010743:Phospholipids / Q000737:chemistry*; D011485:Protein Binding; D013111:Spider Venoms / Q000737:chemistry*; D013314:Stress, Mechanical
D036341:Intercellular Signaling Peptides and Proteins; D008051:Lipid Bilayers; C411249:MTx4 protein, Grammostola spatulata; D010455:Peptides; D010743:Phospholipids; D013111:Spider Venoms