Abstract
While it is accepted that biomembrane asymmetry is generated by proteins and phospholipids distribution, little is known about how electric changes manifested in a monolayer influence functional properties of proteins localized on the opposite leaflet. Herein we used single-molecule electrophysiology and investigated how asymmetric changes in the electrostatics of an artificial lipid membrane monolayer, generated oppositely from where alamethicin - a model voltage-gated ion channel - was added, altered peptide activity. We found that phlorizin, a membrane dipole potential lowering amphiphile, augmented alamethicin activity and transport features, whereas the opposite occurred with RH-421, which enhances the monolayer dipole potential. Further, the monolayer surface potential was decreased via adsorption of sodium dodecyl sulfate, and demonstrated that vectorial modification of it also affected the alamethicin activity in a predictive manner. A new paradigm is suggested according to which asymmetric changes in the monolayer dipole and surface potential extend their effects spatially by altering the intramembrane potential, whose gradient is sensed by distantly located peptides.
Highlights
A key challenge faced by systems biology is to gain an understanding of the physical mechanisms that govern peptide adsorption, insertion and activity into lipid membranes
In the view of recent literature, a great deal of effort is being devoted to studying the regulation mechanisms of membrane protein function by various amphiphiles, at concentrations that are prone to affect the physical properties of lipid membrane
Due to the fact that the large majority of pharmaceuticals are amphiphiles, it stems natural for pharmaceutical development to invest extensive knowledge into studying the effects of amphiphiles on membrane protein function
Summary
A key challenge faced by systems biology is to gain an understanding of the physical mechanisms that govern peptide adsorption, insertion and activity into lipid membranes. It is well established that the membrane electrostatics has the potential of modulating manifestations of a wide selection of membrane proteins, including voltage-gated ion channels [3], enzymes [4], ligand-gated channels [5], antimicrobial peptides [6] and Gprotein-coupled receptors [7]. 2436108 V/m and plays important roles in cellular physiology, such as the translocation of hydrophobic ions through lipidic bilayers [8], it modulates the activity of phospholipase A2 [10], it alters the extent of the membrane fusion [11], as well as the insertion and channel forming activity and single channel properties of peptides and proteins (vide infra). The bilayer-induced allosteric regulation of protein function has been remarkably well described explained in studies involving various antimicrobial peptides useful for ion channels representation [13,14,15,16]
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