title: Order and disorder control the functional rearrangement of influenza hemagglutinin.
abstract: Influenza hemagglutinin (HA), a homotrimeric glycoprotein crucial for membrane fusion, undergoes a large-scale structural rearrangement during viral invasion. X-ray crystallography has shown that the pre- and postfusion configurations of HA2, the membrane-fusion subunit of HA, have disparate secondary, tertiary, and quaternary structures, where some regions are displaced by more than 100 Å. To explore structural dynamics during the conformational transition, we studied simulations of a minimally frustrated model based on energy landscape theory. The model combines structural information from both the pre- and postfusion crystallographic configurations of HA2. Rather than a downhill drive toward formation of the central coiled-coil, we discovered an order-disorder transition early in the conformational change as the mechanism for the release of the fusion peptides from their burial sites in the prefusion crystal structure. This disorder quickly leads to a metastable intermediate with a broken threefold symmetry. Finally, kinetic competition between the formation of the extended coiled-coil and C-terminal melting results in two routes from this intermediate to the postfusion structure. Our study reiterates the roles that cracking and disorder can play in functional molecular motions, in contrast to the downhill mechanical interpretations of the "spring-loaded" model proposed for the HA2 conformational transition.
authors.affiliation: Center for Theoretical Biological Physics and.
authors.forename: Xingcheng
authors.initials: X
authors.lastname: Lin
authors.affiliation: Center for Theoretical Biological Physics and.
authors.forename: Nathanial R
authors.initials: NR
authors.lastname: Eddy
authors.affiliation: Center for Theoretical Biological Physics and.
authors.forename: Jeffrey K
authors.initials: JK
authors.lastname: Noel
authors.affiliation: Department of Physics, Northeastern University, Boston, MA 02115; and.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Whitford
authors.affiliation: Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030.
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Center for Theoretical Biological Physics andVerna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030Department of Bioengineering, Rice University, Houston, TX 77005;
authors.forename: Jianpeng
authors.initials: J
authors.lastname: Ma
authors.affiliation: Center for Theoretical Biological Physics and jonuchic@rice.edu.
authors.forename: José N
authors.initials: JN
authors.lastname: Onuchic
mesh_terms: D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000737:chemistry*; D056004:Molecular Dynamics Simulation
chemical_list: D019267:Hemagglutinin Glycoproteins, Influenza Virus
keywords: protein folding; structure-based model
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