A computational model for the electrostatic sequestration of PI(4,5)P2 by membrane-adsorbed basic peptides

The multivalent acidic phospholipid phosphatidylinositol 4,5-bisphosphate (PI(4,5)P-2) 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)P-2 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)P-2 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)P-2 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)P-2; 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)P-2. Our calculations, thus, provide a structural and quantitative description of the observed interaction of PI(4,5)P-2 with membrane-adsorbed basic sequences.