Molecular dynamics study of a gelsolin-derived peptide binding to a lipid bilayer containing phosphatidylinositol 4,5-bisphosphate.
Gelsolin is an actin-severing protein whose action is initiated by Ca(2+) and inhibited by binding to phosphorylated inositol lipid or phosphoinositides. The regions of gelsolin responsible for phosphoinositide binding are comprised of residues 150-169 (G150-169) and 135-142 (G135-142). The corresponding peptides possess similar binding potency as native gelsolin. Their common feature is the presence of arginine and lysine residues that can bind to negatively charged phosphate groups of phosphoinositides. In this work the binding of the G150-169 peptide to a phosphatidylinositol 4,5-bisphosphate (PIP2) cluster in a lipid membrane model was investigated by molecular dynamics calculations (MD) with the AMBER 4.1 force field, taking into account explicit solvent molecules. Initially the structure of G150-169 was simulated by using the electrostatically driven Monte Carlo (EDMC) and MD methods, and the resulting structure agreed within 3.7 A backbone-atom root mean square deviation with the corresponding experimentally derived structure (PDB code: 1SOL). Using this model for the peptide, a subsequent MD simulation of G150-169 in a periodic box containing a model of dimyristoyl-phosphatidylcholine (DMPC) lipids with a cluster of four PIP2 molecules was carried out. During the simulation G150-169 interacted strongly with PIP2 molecules, initially by formation of salt bridges between its N-terminal basic groups and the phosphate groups of PIP2, followed by formation of hydrophobic bonds between the hydrophobic side chains of the peptide and the fatty acid tail of the lipid. As a result of the formation of hydrophobic bonds, the PIP2 molecules were pulled out from the lipid bilayer. This mode of binding differs from those of other PIP2-binding protein motifs such as PH domains that interact solely with the hydrophilic head group of PIP2. These results suggest that dissociation of gelsolin from actin by PIP2 lipids may involve entering of the PIP2 molecules to the gelsolin-actin interface, thereby weakening the interactions between these proteins.
Liepiņa
Inta
I
Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga, LV1006, Latvia.
Czaplewski
Cezary
C
Janmey
Paul
P
Liwo
Adam
A
D001665:Binding Sites; D003198:Computer Simulation; D004134:Dimyristoylphosphatidylcholine / Q000737:chemistry*; D018260:Gelsolin / Q000737:chemistry*; D008051:Lipid Bilayers / Q000737:chemistry*; D008958:Models, Molecular; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry*; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000737:chemistry*; D011487:Protein Conformation; D017433:Protein Structure, Secondary
D018260:Gelsolin; D008051:Lipid Bilayers; D010455:Peptides; D019269:Phosphatidylinositol 4,5-Diphosphate; D004134:Dimyristoylphosphatidylcholine