BINDING OF SMALL BASIC PEPTIDES TO MEMBRANES CONTAINING ACIDIC LIPIDS- THEORETICAL-MODELS AND EXPERIMENTAL RESULTS

We measured directly the binding of Lys(3), Lys(5), and Lys(7) to vesi cles containing acidic phospholipids. When the vesicles contain 33% ac idic lipids and the aqueous solution contains 100 mM monovalent salt, the standard Gibbs free energy for the binding of these peptides is 3, 5, and 7 kcal/mol, respectively. The binding energies decrease as the mol% of acidic lipids in the membrane decreases and/or as the salt co ncentration increases. Several lines of evidence suggest that these hy drophilic peptides do not penetrate the polar headgroup region of the membrane and that the binding is mainly due to electrostatic interacti ons, To calculate the binding energies from classical electrostatics, we applied the nonlinear Poisson-Boltzmann equation to atomic models o f the phospholipid bilayers and the basic peptides in aqueous solution , The electrostatic free energy of interaction, which arises from both a long-range coulombic attraction between the positively charged pept ide and the negatively charged lipid bilayer, and a short-range Born o r image charge repulsion, is a minimum when similar to 2.5 Angstrom (i .e., one layer of water) exists between the van der Waals surfaces of the peptide and the lipid bilayer, The calculated molar association co nstants, K, agree well with the measured values: K is typically about 10-fold smaller than the experimental value (i.e., a difference of abo ut 1.5 kcal/mol in the free energy of binding). The predicted dependen ce of K (or the binding free energies) on the ionic strength of the so lution, the mol% of acidic lipids in the membrane, and the number of b asic residues in the peptide agree very well with the experimental mea surements. These calculations are relevant to the membrane binding of a number of important proteins that contain clusters of basic residues .