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Principal Investigator: JOSHUA ZIMMERBERG
Organization: EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
Fiscal Year: 2023
Award: $1,395,355
Funding agency: Eunice Kennedy Shriver National Institute of Child Health and Human Development
In the first paper reporting this discovery, a study of the membrane mechanisms by which the influenza virus can disrupt a target membrane, we establish that FPs underly this disruption: in target membranes, a reversible pore forms upon addition of FP in the absence of virus or even the rest of HA. In MD simulations crafted to understand the chemistry by which FPs act, a third kind of rosette emerged: the aggregation of FP via their lateral side chains (not their hydrophobic surfaces) into FP microdomains that displace lipids in the cis leaflet. This aggregated structure locally thinned the bilayer and significantly increased the probability of water entry. A new model is proposed to explain our data based on a tilting of FPs towards each other to further thin the remaining lipids immediately under even an FP dimer. For larger aggregates, this more hydrated, thinner membrane structure replaces the lipid bilayer in a small domain wherein a lipidic pore can form.
A second paper on the membrane mechanisms by which the influenza virus can disrupt a target membrane. The fusion peptide (FP) domain is necessary for the fusogenic activity of spike proteins in a variety of enveloped viruses, allowing the virus to infect the host cell, and is the only part of the protein that interacts directly with the target membrane lipid tails during fusion. There are consistent findings of poration by this domain in experimental model membrane systems, and, in certain conditions, the isolated FPs can generate pores. Here, we use molecular dynamics simulations to investigate the specifics of how these FP-induced pores form in membranes with different compositions of lysolipid and POPC. The simulations show that pores form spontaneously at high lysolipid concentrations via hybrid intermediates, where FP aggregates in the cis leaflet tilt to form a funnel-like structure that spans the leaflet and locally reduces the hydrophobic thickness that must be traversed by water to form a pore. By restraining a single FP within an FP aggregate to this tilted conformation, pores can be formed in lower-lysolipid-content membranes, including pure POPC, on the 100-ns timescale, much more rapidly than in unbiased simulations in bilayers with the same composition. The pore formation pathway is similar to the spontaneous formation in high lysolipid
concentrations. Depending on the membrane composition, the pores can be metastable (as seen in POPC) or lead to membrane rupture.
Terms: <Agreement><Amino Acids><Antigens><Cell Body><Cell Membrane Lipids><Cell membrane><Cells><Chemistry><Cytoplasm><Cytoplasmic Membrane><Data><Electron Microscopy><Experimental Models><German Measles><Glycoproteins><Grippe><Hemagglutinin><Hybrids><Hydration><Hydration status><Hydrogen Oxide><Hydrophobic Surfaces><Hydrophobicity><In Vitro><Infection><Influenza><Influenza Virus><Lateral><Lead><Leanness><Lipid Bilayers><Lipids><Mediating><Membrane><Membrane Fusion><Membrane Lipids><Membrane Transport><Modeling><Molecular Configuration><Molecular Conformation><Molecular Dynamics Simulation><Molecular Stereochemistry><Morbidity><Morbidity - disease rate><N-terminal><NH2-terminal><Paper><Pathway interactions><Pb element><Peptide Domain><Peptides><Phosphatides><Phospholipids><Plasma Membrane><Probability><Protein Domains><Proteins><Rabies><Receptor Protein><Reporting><Rest><Role><Rubella><Rupture><Side><Structure><Surface><System><TM Domain><Tail><Tertiary Protein Structure><Therapeutic><Thick><Thickness><Thinness><Transmembrane Domain><Transmembrane Region><Transmembrane Transport><Variant><Variation><Viral><Viral Diseases><Viral Fusion Proteins><Viral Genome><Virus><Virus Assembly><Virus Diseases><Visualization><Water><aminoacid><amphiphilicity><conformation><conformational><conformational state><conformationally><conformations><dimer><flu serotype><flu strain><flu subtype><flu viral strain><flu virus strain><heavy metal Pb><heavy metal lead><immunogen><in vivo><influenza serotype><influenza strain><influenza subtype><influenza viral strain><influenza virus strain><influenzavirus><lipid bilayer membrane><lyssa><membrane model><membrane structure><molecular dynamics><mortality><pathway><plasmalemma><receptor><restraint><simulation><social role><viral assembly><viral infection><virus genome><virus infection><virus-induced disease>