Atomistic simulations indicate the functional loop-to-coiled-coil transition in influenza hemagglutinin is not downhill

Proc Natl Acad Sci U S A. 2018 Aug 21;115(34):E7905-E7913. doi: 10.1073/pnas.1805442115. Epub 2018 Jul 16.

Abstract

Influenza hemagglutinin (HA) mediates viral entry into host cells through a large-scale conformational rearrangement at low pH that leads to fusion of the viral and endosomal membranes. Crystallographic and biochemical data suggest that a loop-to-coiled-coil transition of the B-loop region of HA is important for driving this structural rearrangement. However, the microscopic picture for this proposed "spring-loaded" movement is missing. In this study, we focus on understanding the transition of the B loop and perform a set of all-atom molecular dynamics simulations of the full B-loop trimeric structure with the CHARMM36 force field. The free-energy profile constructed from our simulations describes a B loop that stably folds half of the postfusion coiled coil in tens of microseconds, but the full coiled coil is unfavorable. A buried hydrophilic residue, Thr59, is implicated in destabilizing the coiled coil. Interestingly, this conserved threonine is the only residue in the B loop that strictly differentiates between the group 1 and 2 HA molecules. Microsecond-scale constant temperature simulations revealed that kinetic traps in the structural switch of the B loop can be caused by nonnative, intramonomer, or intermonomer β-sheets. The addition of the A helix stabilized the postfusion state of the B loop, but introduced the possibility for further β-sheet structures. Overall, our results do not support a description of the B loop in group 2 HAs as a stiff spring, but, rather, it allows for more structural heterogeneity in the placement of the fusion peptides during the fusion process.

Keywords: B-loop transition; all-atom molecular dynamics; buried water; sequence divergence; structural heterogeneity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Hemagglutinin Glycoproteins, Influenza Virus / chemistry*
  • Hemagglutinin Glycoproteins, Influenza Virus / metabolism
  • Influenza A virus / chemistry*
  • Influenza A virus / metabolism
  • Molecular Dynamics Simulation*
  • Protein Structure, Quaternary
  • Protein Structure, Secondary

Substances

  • Hemagglutinin Glycoproteins, Influenza Virus