title: The "electrostatic-switch" mechanism: Monte Carlo study of MARCKS-membrane interaction.
abstract: The binding of the myristoylated alanine-rich C kinase substrate (MARCKS) to mixed, fluid, phospholipid membranes is modeled with a recently developed Monte Carlo simulation scheme. The central domain of MARCKS is both basic (zeta = +13) and hydrophobic (five Phe residues), and is flanked with two long chains, one ending with the myristoylated N-terminus. This natively unfolded protein is modeled as a flexible chain of "beads" representing the amino acid residues. The membranes contain neutral (zeta = 0), monovalent (zeta = -1), and tetravalent (zeta = -4) lipids, all of which are laterally mobile. MARCKS-membrane interaction is modeled by Debye-Hückel electrostatic potentials and semiempirical hydrophobic energies. In agreement with experiment, we find that membrane binding is mediated by electrostatic attraction of the basic domain to acidic lipids and membrane penetration of its hydrophobic moieties. The binding is opposed by configurational entropy losses and electrostatic membrane repulsion of the two long chains, and by lipid demixing upon adsorption. The simulations provide a physical model for how membrane-adsorbed MARCKS attracts several PIP(2) lipids (zeta = -4) to its vicinity, and how phosphorylation of the central domain (zeta = +13 to zeta = +7) triggers an "electrostatic switch", which weakens both the membrane interaction and PIP(2) sequestration. This scheme captures the essence of "discreteness of charge" at membrane surfaces and can examine the formation of membrane-mediated multicomponent macromolecular complexes that function in many cellular processes.
authors.affiliation: Department of Physical Chemistry and The Fritz Haber Research Center, Hebrew University of Jerusalem, Jerusalem 91904, Israel.
authors.forename: Shelly
authors.initials: S
authors.lastname: Tzlil
authors.forename: Diana
authors.initials: D
authors.lastname: Murray
authors.forename: Avinoam
authors.initials: A
authors.lastname: Ben-Shaul
mesh_terms: D003198:Computer Simulation; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry*; D008051:Lipid Bilayers / Q000737:chemistry*; D008560:Membrane Fluidity; D008565:Membrane Proteins / Q000737:chemistry* / Q000648:ultrastructure*; D008956:Models, Chemical; D008958:Models, Molecular; D009010:Monte Carlo Method; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D010743:Phospholipids / Q000737:chemistry*; D011487:Protein Conformation; D055672:Static Electricity
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008051:Lipid Bilayers; D008565:Membrane Proteins; D010743:Phospholipids; D000076250:Myristoylated Alanine-Rich C Kinase Substrate