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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