Conformational Partitioning of the Fusion Peptide of HIV-1 gp41 and Its Structural Analogs in Bilayer Membranes (original) (raw)
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Biochimica et Biophysica Acta (BBA) - Biomembranes, 2008
Fourier-transformed infrared spectroscopy (FTIR) and molecular dynamics (MD) simulation results are presented to support our hypothesis that the conformation and the oligomeric state of the HIV-1 gp41 fusion domain or fusion peptide (gp41-FP) are determined by the membrane surface area per lipid (APL), which is affected by the membrane curvature. FTIR of the gp41-FP in the Aerosol-OT (AOT) reversed micellar system showed that as APL decreases from ∼ 50 to 35 Å 2 by varying the AOT/water ratio, the FP changes from the monomeric α-helical to the oligomeric β-sheet structure. MD simulations in POPE lipid bilayer systems showed that as the APL decreases by applying a negative surface tension, helical monomers start to unfold into turn-like structures. Furthermore, an increase in the applied lateral pressure during nonequilibrium MD simulations favored the formation of β-sheet structure. These results provide better insight into the relationship between the structures of the gp41-FP and the membrane, which is essential in understanding the membrane fusion process. The implication of the results of this work on what is the fusogenic structure of the HIV-1 FP is discussed.
Adopted Conformations in Membranes by the HIV1 Fusion Peptide
2010
The human immunodeficiency virus type 1 (HIV-1) fusion peptide spans a sequence of ca. 25 amino acid residues located at the N terminus of the spike transmembrane subunit gp41. This hydrophobic and conserved domain is required for the induction of the cell-virus membrane fusion event that initiates the replication cycle. HIV-1 fusion peptide-membrane interactions have been studied using synthetic derivatives and model membranes. This chapter focuses on the description of two interrelated aspects of this approach: (1) membrane destabilization (function) detected as permeabilization or fusion of vesicles, or both, with defined lipid composition, and (2) adopted conformation (structure) by the peptide associated with the same model membranes.
HIV-1 Fusion Peptide Decreases Bending Energy and Promotes Curved Fusion Intermediates
Biophysical Journal, 2007
A crucial step in human immunodeficiency virus (HIV) infection is fusion between the viral envelope and the T-cell membrane, which must involve intermediate membrane states with high curvature. Our main result from diffuse x-ray scattering is that the bending modulus K C is greatly reduced upon addition of the HIV fusion peptide FP-23 to lipid bilayers. A smaller bending modulus reduces the free energy barriers required to achieve and pass through the highly curved intermediate states and thereby facilitates fusion and HIV infection. The reduction in K C is by a factor of 13 for the thicker, stiffer 1,2-sn-dierucoylphosphatidylcholine bilayers and by a factor of 3 for 1,2-sn-dioleoylphosphatidylcholine bilayers. The reduction in K C decays exponentially with concentration of FP-23, and the 1/e concentration is ,1 mol % peptide/lipid, which is well within the physiological range for a fusion site. A secondary result is, when FP-23 is added to the samples which consist of stacks of membranes, that the distance between membranes increases and eventually becomes infinite at full hydration (unbinding); we attribute this both to electrostatic repulsion of the positively charged arginine in the FP-23 and to an increase in the repulsive fluctuation interaction brought about by the smaller K C . Although this latter interaction works against membrane fusion, our results show that the energy that it requires of the fusion protein machinery to bring the HIV envelope membrane and the target T-cell membrane into close contact is negligible.
European Biophysics Journal With Biophysics Letters, 2011
To better understand peptide-induced membrane fusion at a molecular level, we set out to determine the structure of the fusogenic peptide FP23 from the HIV-1 protein gp41 when bound to a lipid bilayer. An established solid-state 19F nuclear magnetic resonance (NMR) approach was used to collect local orientational constraints from a series of CF3-phenylglycine-labeled peptide analogues in macroscopically aligned membranes.
Determinants of Membrane Activity from Mutational Analysis of the HIV Fusion Peptide
Biochemistry, 2011
b S Supporting Information W e set out to dissect the origins of biophysical membrane activity in the HIV fusion peptide sequence. HIV membrane fusion 1,2 is mediated by the surface glycoprotein gp41, which is exposed following receptor binding. 3À7 A series of elegant experiments revealed a "spring-loaded" mechanism in which gp41 undergoes a dramatic conformational transformation that launches its previously buried N-terminal fusion peptide domain into the host membrane. 8À10 This 23-residue peptide is critical for viral infectivity 11À14 and itself can induce membrane fusion. 15À17 Conceptually, hydration repulsion barriers 18 must be overcome to allow membranes to dock; maturation of docking into fusion requires stabilization of either positive or negative membrane curvature, 19À22 which lowers the energy barrier to formation of a lipid membrane "fusion stalk", 18,23 a key intermediate in fusion. Consistent with this mechanism, the HIV fusion peptide has been reported to decrease the energy required to bend synthetic membranes, 24 though it is not clear how this could be generalized to unrelated fusion peptides. 25À27 The influenza virus 28À30 fusion peptide shares little sequence homology the HIV fusion sequence other than high glycine content, 31 though this is not a universal property among viral fusion peptides. 25 Fusogenic secondary structures have been proposed that are R-helical, β-sheet, or alternately helical and β-sheet; there is also considerable evidence that suggests that fusion peptides are unstructured in their functional form. 32À40 Given the diversity of primary structures in viral fusion peptides, it seems unlikely that they may all coalesce into the same functional secondary structure; an alternative explanation is that fusogenic function might be imparted at the level of general physical properties
Biochimica et Biophysica Acta (BBA) - Biomembranes, 2011
One way to gain information about the fusogenic potential of virus-derived synthetic peptides is to examine their interfacial properties and subsequently to study them in monolayers and bilayers. Here, we characterize the physicochemical surface properties of the peptide E1(64-81), whose sequence is AQLVGELGSLYGPLSVSA. This peptide is derived from the E1 structural protein of GBV-C/HGV which was previously shown to inhibit leakage of vesicular contents caused by the HIV-1 fusion peptide (HIV-1 FP). Mixed isotherms of E1(64-81) and HIV-1 FP were obtained and their Brewster angle microscopy (BAM) and atomic force microscopy (AFM) images showed that the peptide mixture forms a different structure that is not present in the pure peptide images. Studies with lipid monolayers (1,2-dimyristoyl-sn-glycero-3-[phospho-rac-(1-glycerol)] (DMPG) and 1,2-dipalmitoyl-sn-glycero-3-phospho-rac-(1-glycerol) (DPPG)) show that both peptides interact with all the lipids assayed but the effect that HIV-1 FP has on the monolayers is reduced in the presence of E1(64-81). Moreover, differential scanning calorimetry (DSC) experiments show the capacity of HIV-1 FP to modify the properties of the bilayer structure and the capacity of E1(64-81) to inhibit these modifications. Our results indicate that E1(64-81) interacts with HIV-1 FP to form a new structure, and that this may be the cause of the previously observed inhibition of the activity of HIV-1 FP by E1(64-81). j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / b b a m e m
Line tension at lipid phase boundaries as driving force for HIV fusion peptide-mediated fusion
Nature communications, 2016
Lipids and proteins are organized in cellular membranes in clusters, often called 'lipid rafts'. Although raft-constituent ordered lipid domains are thought to be energetically unfavourable for membrane fusion, rafts have long been implicated in many biological fusion processes. For the case of HIV gp41-mediated membrane fusion, this apparent contradiction can be resolved by recognizing that the interfaces between ordered and disordered lipid domains are the predominant sites of fusion. Here we show that line tension at lipid domain boundaries contributes significant energy to drive gp41-fusion peptide-mediated fusion. This energy, which depends on the hydrophobic mismatch between ordered and disordered lipid domains, may contribute tens of kBT to fusion, that is, it is comparable to the energy required to form a lipid stalk intermediate. Line-active compounds such as vitamin E lower line tension in inhomogeneous membranes, thereby inhibit membrane fusion, and thus may be us...
Biophysical Journal, 2004
We consider the elastic behavior of flat lipid monolayer embedding cylindrical inclusions oriented obliquely with respect to the monolayer plane. An oblique inclusion models a fusion peptide, a part of a specialized protein capable of inducing merger of biological membranes in the course of fundamental cellular processes. Although the crucial importance of the fusion peptides for membrane merger is well established, the molecular mechanism of their action remains unknown. This analysis is aimed at revealing mechanical deformations and stresses of lipid monolayers induced by the fusion peptides, which, potentially, can destabilize the monolayer structure and enhance membrane fusion. We calculate the deformation of a monolayer embedding a single oblique inclusion and subject to a lateral tension. We analyze the membrane-mediated interactions between two inclusions, taking into account bending of the monolayer and tilt of the hydrocarbon chains with respect to the surface normal. In contrast to a straightforward prediction that the oblique inclusions should induce tilt of the lipid chains, our analysis shows that the monolayer accommodates the oblique inclusion solely by bending. We find that the interaction between two inclusions varies nonmonotonically with the interinclusion distance and decays at large separations as square of the distance, similar to the electrostatic interaction between two electric dipoles in two dimensions. This long-range interaction is predicted to dominate the other interactions previously considered in the literature.
New Journal of Physics, 2011
The fusion peptide (FP) of the human immunodeficiency virus (HIV) is part of the N-terminus of the viral envelope glycoprotein gp41 and is believed to play an important role in the viral entry process. To understand the immediate effect of this peptide on the cell membrane, we have studied the influence of the synthetic FP sequence FP23 on the mechanical properties of model lipid bilayers. For this purpose, giant unilamellar vesicles were prepared from the unsaturated lipid dioleoylphosphatidylcholine mixed in various molar ratios with FP23. The bending stiffness of the vesicles was measured with two different methods: fluctuation analysis and aspiration with micropipettes. The data obtained from both of these approaches show that the bending stiffness of the membrane decreases gradually with increasing concentration of the FP23 in the bilayer. Low concentrations of only a few mol% FP23 are sufficient to decrease the bending stiffness of the lipid bilayer by about a factor of 2. Finally, data obtained for the stretching elasticity modulus of the membrane suggest that the peptide insertion decreases the coupling between the two leaflets of the bilayer.
Influenza virus is one of the most devastating human pathogens. In order to infect host cells, this virus fuses its membrane with the host membrane in a process mediated by the glycoprotein hemagglutinin. During fusion, the Nterminal region of hemagglutinin, which is known as the fusion peptide (FP), inserts into the host membrane, promoting lipid mixing between the viral and host membranes. Therefore, this peptide plays a key role in the fusion process, but the exact mechanism by which it promotes lipid mixing is still unclear. To shed light into this matter, we performed molecular dynamics (MD) simulations of the influenza FP in different environments (water, dodecylphosphocholine (DPC) micelles, and a dimyristoylphosphatidylcholine (DMPC) membrane). While in pure water the peptide lost its initial secondary structure, in simulations performed in the presence of DPC micelles it remained stable, in agreement with previous experimental observations. In simulations performed in the presence of a preassembled DMPC bilayer, the peptide became unstructured and was unable to insert into the membrane as a result of technical limitations of the method used. To overcome this problem, we used a self-assembly strategy, assembling the membrane together with the peptide. These simulations revealed that the peptide can adopt a membrane-spanning conformation, which had not been predicted by previous MD simulation studies. The peptide insertion had a strong effect on the membrane, lowering the bilayer thickness, disordering nearby lipids, and promoting lipid tail protrusion. These results contribute to a better understanding of the role of the FP in the fusion process.