title: HIV fusion peptide penetrates, disorders, and softens T-cell membrane mimics.
abstract: This work investigates the interaction of N-terminal gp41 fusion peptide (FP) of human immunodeficiency virus type 1 (HIV-1) with model membranes in order to elucidate how FP leads to fusion of HIV and T-cell membranes. FP constructs were (i) wild-type FP23 (23 N-terminal amino acids of gp41), (ii) water-soluble monomeric FP that adds six lysines on the C-terminus of FP23 (FPwsm), and (iii) the C-terminus covalently linked trimeric version (FPtri) of FPwsm. Model membranes were (i) LM3 (a T-cell mimic), (ii) 1,2-dioleoyl-sn-glycero-3-phosphocholine, (iii) 1,2-dioleoyl-sn-glycero-3-phosphocholine/30 mol% cholesterol, (iv) 1,2-dierucoyl-sn-glycero-3-phosphocholine, and (v) 1,2-dierucoyl-sn-glycero-3-phosphocholine/30 mol% cholesterol. Diffuse synchrotron low-angle x-ray scattering from fully hydrated samples, supplemented by volumetric data, showed that FP23 and FPtri penetrate into the hydrocarbon region and cause membranes to thin. Depth of penetration appears to depend upon a complex combination of factors including bilayer thickness, presence of cholesterol, and electrostatics. X-ray data showed an increase in curvature in hexagonal phase 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine, which further indicates that FP23 penetrates into the hydrocarbon region rather than residing in the interfacial headgroup region. Low-angle x-ray scattering data also yielded the bending modulus K(C), a measure of membrane stiffness, and wide-angle x-ray scattering yielded the S(xray) orientational order parameter. Both FP23 and FPtri decreased K(C) and S(xray) considerably, while the weak effect of FPwsm suggests that it did not partition strongly into LM3 model membranes. Our results are consistent with the HIV FP disordering and softening the T-cell membrane, thereby lowering the activation energy for viral membrane fusion.
authors.affiliation: Biological Physics Group, Department of Physics, Carnegie Mellon University, Pittsburgh, PA 15213, USA. stn@cmu.edu
authors.forename: Stephanie
authors.initials: S
authors.lastname: Tristram-Nagle
authors.forename: Rob
authors.initials: R
authors.lastname: Chan
authors.forename: Edgar
authors.initials: E
authors.lastname: Kooijman
authors.forename: Pradeep
authors.initials: P
authors.lastname: Uppamoochikkal
authors.forename: Wei
authors.initials: W
authors.lastname: Qiang
authors.forename: David P
authors.initials: DP
authors.lastname: Weliky
authors.forename: John F
authors.initials: JF
authors.lastname: Nagle
mesh_terms: D032701:Biomimetics; D002152:Calorimetry, Differential Scanning; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism*; D015700:HIV Envelope Protein gp41 / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism*; D008561:Membrane Fusion; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism*; D013601:T-Lymphocytes; D013816:Thermodynamics; D014961:X-Ray Diffraction
chemical_list: D015700:HIV Envelope Protein gp41; D008051:Lipid Bilayers; D010446:Peptide Fragments