title: Interactions of the pleckstrin homology domain with phosphatidylinositol phosphate and membranes: characterization via molecular dynamics simulations.
abstract: The mechanism of interaction of pleckstrin homology (PH) domains with phosphatidylinositol 4,5-bisphosphate (PIP 2)-containing lipid bilayers remains uncertain. While crystallographic studies have emphasized PH-inositol 1,4,5-trisphosphate (IP 3) interactions, biophysical studies indicate a degree of less specific protein-bilayer interactions. We have used molecular dynamics simulations to characterize the interactions of the PH domain from phospholipase C-delta1 with IP 3 and with PIP 2, the latter in lipid bilayers and in detergent micelles. Simulations of the PH domain in water reveal a reduction in protein flexibility when IP 3 is bound. Simulations of the PH domain bound to PIP 2 in lipid bilayers indicate a tightening of ligand-protein interactions relative to the PH-IP 3 complex, alongside formation of H-bonds between PH side chains and lipid (PC) headgroups, and a degree of penetration of hydrophobic side chains into the core of the bilayer. Comparison with simulations of the PH-bound domain to a PC bilayer in the absence of PIP 2 suggests that the presence of PIP 2 increases the extent of PH-membrane interactions. Thus, comparative molecular dynamics simulations reveal how a PI-binding domain undergoes changes in conformational dynamics on binding to a PIP 2-containing membrane and how interactions additional to those with the PI headgroup are formed.
authors.affiliation: Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
authors.forename: Emi
authors.initials: E
authors.lastname: Psachoulia
authors.forename: Mark S P
authors.initials: MS
authors.lastname: Sansom
mesh_terms: D003198:Computer Simulation; D018360:Crystallography, X-Ray; D008024:Ligands; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D010710:Phosphates / Q000737:chemistry; D018129:Phosphatidylinositol Phosphates / Q000737:chemistry* / Q000378:metabolism*; D054803:Phospholipase C delta / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary; D014867:Water / Q000737:chemistry
chemical_list: D008024:Ligands; D008051:Lipid Bilayers; D010710:Phosphates; D018129:Phosphatidylinositol Phosphates; D014867:Water; D054803:Phospholipase C delta