Mohamad R. Kalani, Abdulvahab Moradi, Mahmoud Moradi, and Emad Tajkhorshid.
Characterizing a histidine switch controlling pH-dependent
conformational changes of the influenza virus hemagglutinin.
Biophysical Journal, 105:993-1003, 2013.
(PMC: PMC3752100)
KALA2013-ET
During the fusion of the influenza virus to the host cell, bending of the HA2 chain of
hemagglutinin into a hairpin-shaped structure in a pH-dependent manner facilitates the
fusion of the viral envelope and the endosomal membrane. To characterize the structural
and dynamical responses of the hinge region of HA2 to pH changes and examine the role
of a conserved histidine in this region (the hinge histidine), we have performed an
extensive set of molecular dynamics (MD) simulations of 26-residue peptides
encompassing the hinge regions of several hemagglutinin subtypes under both neutral and
low pH conditions, modeled by the change of the protonation state of the hinge histidine.
More than 70 sets of MD simulations (collectively amounting to 25.1 s) were
performed in both implicit and explicit solvents to study the effect of histidine protonation
on structural dynamics of the hinge region. In both explicit and implicit solvent
simulations, hinge bending was consistently observed upon the protonation of the
histidine in all the simulations starting with an initial straight helical conformation, whereas
the systems with a neutral histidine retained their primarily straight conformation
throughout the simulations. Conversely, the MD simulations starting from an initially bent
conformation resulted in the formation of a straight helical structure upon the
neutralization of the hinge histidine, whereas the bent structure was maintained when the
hinge histidine remained protonated. Finally, mutation of the hinge histidine to alanine
abolishes the bending response of the peptide altogether. A molecular mechanism based
on the interaction of the hinge histidine with neighboring acidic residues is proposed to be
responsible for its role in controlling the conformation of the hinge. We propose that this
might present a common mechanism for pH-controlled structural changes in helical
structures when histidines act as the pH sensor.
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