The "Electrostatic-Switch" Mechanism: Monte Carlo Study of MARCKS-Membrane Interaction

¹ California Institute of Technology
² Columbia University, New York,
³ The Hebrew Univ. of Jerusalem

^* To whom correspondence should be addressed. E-mail: abs{at}fh.huji.ac.il.

Submitted on February 29, 2008
Revised on April 7, 2008
Accepted on 25 April 2008

	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 (=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 (=0), monovalent (=-1 ), and tetravalent (=-4 ) lipids, all of which are laterally mobile. MARCKS-membrane interaction is modeled by Debye-Hückel electrostatic potentials and semi-empirical 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 PIP2 lipids (=-4 ) to its vicinity, and how phosphorylation of the central domain (=+13 to ++7) triggers an "electrostatic switch", which weakens both the membrane interaction and PIP2 sequestration. This scheme captures the essence of "discreteness of charge&" at membrane surfaces and can examine the formation of membrane-mediated multi-component macromolecular complexes that function in many cellular processes.

Key Words: Electrostatic-switch, Lipid mobility, MARCKS, Monte-Carlo, membrane