| Abstract
| - The mechanism of interaction of pleckstrin homology (PH) domains with phosphatidylinositol 4,5-bisphosphate (PIP2)-containing lipid bilayers remains uncertain. While crystallographic studies have emphasized PH−inositol 1,4,5-trisphosphate (IP3) 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-δ1 with IP3 and with PIP2, the latter in lipid bilayers and in detergent micelles. Simulations of the PH domain in water reveal a reduction in protein flexibility when IP3 is bound. Simulations of the PH domain bound to PIP2 in lipid bilayers indicate a tightening of ligand−protein interactions relative to the PH−IP3 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 PIP2 suggests that the presence of PIP2 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 PIP2-containing membrane and how interactions additional to those with the PI headgroup are formed.
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