Interactions of the Pleckstrin Homology Domain with Phosphatidylinositol Phosphate and Membranes: Characterization via Molecular Dynamics Simulations Export

@article{citeulike:2553137, abstract = {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 PHinositol 1,4,5-trisphosphate (IP3) interactions, biophysical studies indicate a degree of less specific proteinbilayer interactions. We have used molecular dynamics simulations to characterize the interactions of the PH domain from phospholipase C-´1 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 ligandprotein interactions relative to the PHIP3 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 PHmembrane 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.}, address = {Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, U.K.}, author = {Psachoulia, Emi and Sansom, Mark S.}, citeulike-article-id = {2553137}, citeulike-linkout-0 = {http://dx.doi.org/10.1021/bi702319k}, citeulike-linkout-1 = {http://pubs.acs.org/doi/abs/10.1021/bi702319k}, citeulike-linkout-2 = {http://view.ncbi.nlm.nih.gov/pubmed/18341295}, citeulike-linkout-3 = {http://www.hubmed.org/display.cgi?uids=18341295}, day = {15}, doi = {10.1021/bi702319k}, journal = {Biochemistry}, keywords = {inositiol, md, phosphoinositides, protein-ligand, protein-lipid, protein-membrane, simulations}, month = {March}, number = {14}, pages = {4211--4220}, posted-at = {2008-05-28 22:02:54}, priority = {2}, title = {Interactions of the Pleckstrin Homology Domain with Phosphatidylinositol Phosphate and Membranes: Characterization via Molecular Dynamics Simulations}, url = {http://dx.doi.org/10.1021/bi702319k}, volume = {47}, year = {2008} }

TY - JOUR ID - citeulike:2553137 L3 - citeulike-article-id:2553137 N2 - 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 PHinositol 1,4,5-trisphosphate (IP3) interactions, biophysical studies indicate a degree of less specific proteinbilayer interactions. We have used molecular dynamics simulations to characterize the interactions of the PH domain from phospholipase C-´1 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 ligandprotein interactions relative to the PHIP3 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 PHmembrane 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. IS - 14 JF - Biochemistry AD - Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, U.K. EP - 4220 TI - Interactions of the Pleckstrin Homology Domain with Phosphatidylinositol Phosphate and Membranes: Characterization via Molecular Dynamics Simulations VL - 47 SP - 4211 KW - inositiol KW - md KW - phosphoinositides KW - protein-ligand KW - protein-lipid KW - protein-membrane KW - simulations AU - Psachoulia, Emi AU - Sansom, Mark PY - 2008/03/15/ UR - http://dx.doi.org/10.1021/bi702319k ER -