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A Computational Model for the Electrostatic Sequestration of PI(4,5)P₂ by Membrane-Adsorbed Basic Peptides

Jiyao Wang ^*, Alok Gambhir  , Stuart McLaughlin  and Diana Murray ^*

^* Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, New York 10021; Department of Physiology and Biophysics, Health Sciences Center, and Department of Physics and Astronomy, State University of New York at Stony Brook, Stony Brook, New York 11794

Correspondence: Address reprint requests to Diana Murray, Dept. of Microbiology and Immunology, Weill Medical College of Cornell University, 1300 York Ave., Box 62, New York, NY 10021. Tel.: 212-746-1184; Fax: 212-746-8587; E-mail: dim2007{at}med.cornell.edu.

The multivalent acidic phospholipid phosphatidylinositol 4,5-bisphosphate (PI(4,5)P₂) plays a key role in many biological processes. Recent studies show that unstructured clusters of basic residues from a number of peripheral proteins can laterally sequester PI(4,5)P₂ in membranes. Specifically, experiments suggest that the basic effector domain of the myristoylated alanine-rich C kinase substrate (MARCKS), or a peptide corresponding to this domain, MARCKS(151–175), sequesters several PI(4,5)P₂ and that this sequestration is due to nonspecific electrostatic interactions. Here, we use the finite difference Poisson-Boltzmann method to test this hypothesis by calculating the electrostatic free energy of lateral sequestration of PI(4,5)P₂ by membrane-adsorbed basic peptides: Lys-7, Lys-13, and FA-MARCKS(151–175), a peptide based on MARCKS(151–175). In agreement with experiments, we find that the electrostatic free energy becomes more favorable when: 1), Lys-13 and FA-MARCKS(151–175) sequester several PI(4,5)P₂; 2), the linear charge density of the basic peptide increases; 3), the mol percent monovalent acidic lipid in the membrane decreases; and 4), the ionic strength of the solution decreases. In addition, the electrostatic sequestration free energy is in excess of the entropic penalty associated with localizing PI(4,5)P₂. Our calculations, thus, provide a structural and quantitative description of the observed interaction of PI(4,5)P₂ with membrane-adsorbed basic sequences.

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