title: Lowered pH Leads to Fusion Peptide Release and a Highly Dynamic Intermediate of Influenza Hemagglutinin.
abstract: Hemagglutinin (HA), the membrane-bound fusion protein of the influenza virus, enables the entry of virus into host cells via a structural rearrangement. There is strong evidence that the primary trigger for this rearrangement is the low pH environment of a late endosome. To understand the structural basis and the dynamic consequences of the pH trigger, we employed explicit-solvent molecular dynamics simulations to investigate the initial stages of the HA transition. Our results indicate that lowered pH destabilizes HA and speeds up the dissociation of the fusion peptides (FPs). A buried salt bridge between the N-terminus and Asp1122 of HA stem domain locks the FPs and may act as one of the pH sensors. In line with recent observations from simplified protein models, we find that, after the dissociation of FPs, a structural order-disorder transition in a loop connecting the central coiled-coil to the C-terminal domains produces a highly mobile HA. This motion suggests the existence of a long-lived asymmetric or "symmetry-broken" intermediate during the HA conformational change. This intermediate conformation is consistent with models of hemifusion, and its early formation during the conformational change has implications for the aggregation seen in HA activity.
authors.affiliation: Center for Theoretical Biological Physics, Rice University , Houston, Texas 77030, United States.|Department of Physics and Astronomy, Rice University , Houston, Texas 77005, United States.
authors.forename: Xingcheng
authors.initials: X
authors.lastname: Lin
authors.affiliation: Max Delbrück Center for Molecular Medicine , Berlin 13125, Germany.|Fritz Haber Institute of the Max Planck Society , Berlin 14195, Germany.
authors.forename: Jeffrey K
authors.initials: JK
authors.lastname: Noel
authors.affiliation: Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine , Houston 77030, Texas, United States.
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Center for Theoretical Biological Physics, Rice University , Houston, Texas 77030, United States.|Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine , Houston 77030, Texas, United States.|Department of Bioengineering, Rice University , Houston, Texas 77005, United States.
authors.forename: Jianpeng
authors.initials: J
authors.lastname: Ma
authors.affiliation: Center for Theoretical Biological Physics, Rice University , Houston, Texas 77030, United States.|Department of Physics and Astronomy, Rice University , Houston, Texas 77005, United States.|Departments of Chemistry and Biosciences, Rice University , Houston, Texas 77005, United States.
authors.forename: José N
authors.initials: JN
authors.lastname: Onuchic
mesh_terms: D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000737:chemistry*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007251:Influenza, Human; D056004:Molecular Dynamics Simulation; D010455:Peptides / Q000737:chemistry*; D011522:Protons
chemical_list: D019267:Hemagglutinin Glycoproteins, Influenza Virus; D010455:Peptides; D011522:Protons