title: Determinants of membrane activity from mutational analysis of the HIV fusion peptide.
abstract: We have synthesized a small library of 38 variants of the 23-residue fusion peptide domain found at the N-terminus of gp41 glycoprotein of HIV. This hydrophobic, glycine-rich sequence is critical for viral infectivity and is thought to be central in the membrane fusion of viral envelope with the host membrane. There has been extensive discussion regarding the origin of fusogenicity in this viral fusion sequence. Our library of fusion peptide variants was designed to address the biophysical importance of secondary structure, peptide flexibility, glycine content, and placement. We assayed each peptide for its ability to induce lipid mixing and membrane permeablization in synthetic vesicles. We find that the viral fusion peptide may be greatly simplified while retaining fusogenic function and minimizing membrane-permeablizing function; to the best of our knowledge, this is the first attempt to optimize fusogenic function of the HIV fusion peptide through sequence variation. Our data show that many flexible, linear, minimally hydrophobic peptides may achieve the biophysical function of fusion; glycine does not appear to be essential. These findings will be useful in the design of synthetic fusogens for cellular delivery.
authors.affiliation: Department of Chemistry, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Oscar
authors.initials: O
authors.lastname: Torres
authors.forename: Dennis
authors.initials: D
authors.lastname: Bong
mesh_terms: D000595:Amino Acid Sequence; D002462:Cell Membrane / Q000378:metabolism; D002942:Circular Dichroism; D005998:Glycine / Q000737:chemistry / Q000378:metabolism; D015700:HIV Envelope Protein gp41 / Q000737:chemistry* / Q000235:genetics; D008561:Membrane Fusion; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry; D017434:Protein Structure, Tertiary; D014760:Viral Fusion Proteins / Q000737:chemistry* / Q000235:genetics
chemical_list: D015700:HIV Envelope Protein gp41; D010446:Peptide Fragments; D014760:Viral Fusion Proteins; D005998:Glycine