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Lowered pH leads to fusion peptide release and a highly dynamic intermediate of influenza hemagglutinin

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Item Type:Article
Title:Lowered pH leads to fusion peptide release and a highly dynamic intermediate of influenza hemagglutinin
Creators Name:Lin, X.C. and Noel, J.K. and Wang, Q.H. and Ma, J.P. and Onuchic, J.N.
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.
Keywords:Hemagglutinin Glycoproteins, Influenza Virus, Hydrogen-Ion Concentration, Influenza, Human, Molecular Dynamics Simulation, Peptides, Protons
Source:Journal of Physical Chemistry B
ISSN:1520-6106
Publisher:American Chemical Society (U.S.A.)
Volume:120
Number:36
Page Range:9654-9660
Date:15 September 2016
Official Publication:https://doi.org/10.1021/acs.jpcb.6b06775
External Fulltext:View full text on PubMed Central
PubMed:View item in PubMed

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