title: pH-Triggered, Macromolecule-Sized Poration of Lipid Bilayers by Synthetically Evolved Peptides.
abstract: pH-triggered membrane-permeabilizing peptides could be exploited in a variety of applications, such as to enable cargo release from endosomes for cellular delivery, or as cancer therapeutics that selectively permeabilize the plasma membranes of malignant cells. Such peptides would be especially useful if they could enable the movement of macromolecules across membranes, a rare property in membrane-permeabilizing peptides. Here we approach this goal by using an orthogonal high-throughput screen of an iterative peptide library to identify peptide sequences that have the following two properties: (i) little synthetic lipid membrane permeabilization at physiological pH 7 at high peptide concentration and (ii) efficient formation of macromolecule-sized defects in synthetic lipid membranes at acidic pH 5 and low peptide concentration. The peptides we selected are remarkably potent macromolecular sized pore-formers at pH 5, while having little or no activity at pH 7, as intended. The action of these peptides likely relies on tight coupling between membrane partitioning, α-helix formation, and electrostatic repulsions between acidic side chains, which collectively drive a sharp pH-triggered transition between inactive and active configurations with apparent pKavalues of 5.5-5.8. This work opens new doors to developing applications that utilize peptides with membrane-permeabilizing activities that are triggered by physiologically relevant decreases in pH.
authors.affiliation: Department of Materials Science and Engineering, Johns Hopkins University , Baltimore, Maryland 21218, United States.|Institute for NanoBioTechnology, Johns Hopkins University , Baltimore, Maryland 21218, United States.
authors.forename: Gregory
authors.initials: G
authors.lastname: Wiedman
authors.affiliation: Graduate Program in Molecular Biophysics, Johns Hopkins University , Baltimore, Maryland 21218, United States.|Institute for NanoBioTechnology, Johns Hopkins University , Baltimore, Maryland 21218, United States.
authors.forename: Sarah Y
authors.initials: SY
authors.lastname: Kim
authors.affiliation: Graduate Program in Molecular Biophysics, Johns Hopkins University , Baltimore, Maryland 21218, United States.|Institute for NanoBioTechnology, Johns Hopkins University , Baltimore, Maryland 21218, United States.
authors.forename: Elmer
authors.initials: E
authors.lastname: Zapata-Mercado
authors.affiliation: Department of Biochemistry and Molecular Biology, Tulane University School of Medicine , New Orleans, Louisiana 70112, United States.
authors.forename: William C
authors.identifier: 0000-0003-2967-5186
authors.initials: WC
authors.lastname: Wimley
authors.affiliation: Department of Materials Science and Engineering, Johns Hopkins University , Baltimore, Maryland 21218, United States.|Graduate Program in Molecular Biophysics, Johns Hopkins University , Baltimore, Maryland 21218, United States.|Institute for NanoBioTechnology, Johns Hopkins University , Baltimore, Maryland 21218, United States.
authors.forename: Kalina
authors.initials: K
authors.lastname: Hristova
mesh_terms: D006863:Hydrogen-Ion Concentration; D008051:Lipid Bilayers / Q000737:chemistry*; D008954:Models, Biological; D010316:Particle Size; D019151:Peptide Library; D010455:Peptides / Q000737:chemistry*; D016062:Porosity
chemical_list: D008051:Lipid Bilayers; D019151:Peptide Library; D010455:Peptides