1654
Langmuir 2008, 24, 1654-1658
Hydrogen Bonding and Binding of Polybasic Residues with Negatively Charged Mixed Lipid Monolayers Christian D. Lorenz,† Jordi Faraudo,‡ and Alex Travesset*,§ Materials Research Group, Engineering DiVision, King’s College, London Strand, London WC2R 2LS, U.K., Institut de Cie` ncia de Materials de Barcelona (ICMAB-CSIC), Campus de la UAB, E-08193 Bellaterra, Spain, and Department of Physics and Astronomy and Ames Laboratory, Iowa State UniVersity, Ames, Iowa 50011 ReceiVed NoVember 14, 2007. In Final Form: December 29, 2007 Phosphoinositides, phosphorylated products of phosphatidylinositol, are a family of phospholipids present in tiny amounts (1% or less) in the cytosolic surface of cell membranes, yet they play an astonishingly rich regulatory role, particularly in signaling processes. In this letter, we use molecular dynamics simulations on a model system of mixed lipid monolayers to investigate the interaction of phosphatidylinositol 4,5-bisphosphate (PIP2), the most common of the phosphoinositides, with a polybasic peptide consisting of 13 lysines. Our results show that the polybasic peptide sequesters three PIP2 molecules, forming a complex stabilized by the formation of multiple hydrogen bonds between PIP2 and the Lys residues. We also show that the polybasic peptide does not sequester other charged phospholipids such as phosphatidylserine because of the inability to form long-lived stable hydrogen bonds.
Introduction Langmuir monolayers consisting of two or more film-forming components (mixed monolayers) have received much attention as model systems for understanding mechanisms and interactions operating in self-assembled structures relevant to the chemical and pharmaceutical industries.1,2 They are also very interesting as model systems in membrane biophysics, allowing the characterization of physicochemical interactions in a well-defined environment.2 The study presented here explores the intermolecular interactions between a mixed lipid monolayer containing a small amount of a biologically functional lipid (phosphatidylinositol 4,5-bisphosphate, or PIP2), and a polybasic peptide consisting of 13 lysines. PIP2 is the most well-known example of phosphoinositides (PtdIns), a family of phospholipids present in tiny amounts (1% or less) in the cytosolic surface of cell membranes. In spite of their low concentration, phosphoinositides play a key role in nearly all aspects of cell physiology including activation of ion channels, endocytosis, phagocytosis, vesicle trafficking or cytoskeletal attachment.3-5 It has been proposed that specific proteins (such as MARCKS or GAP43 in the case of PIP2) sequester the precious phosphoinositides at the plasma membrane, thus protecting them until required for function. The existing evidence strongly suggests that the sequestering mechanism is driven by “nonspecific electrostatics”, that is, simple Coulomb attraction between the strongly negatively charged PIP2 and basic (positively charged) residues of the proteins.4 The composition of the plasma membrane contains also other negatively charged phospholipids such as phosphatidylserine (PS), present in larger quantities than PIP2 (15-30% versus
