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Characterizing the Molecular Mechanism of the Histidine Switch Model in Influenza Virus Hemagglutinin

Kalani, M.R. and Moradi, A. and Moradi, M. and Tajkhorshid, E. (2013) Characterizing the Molecular Mechanism of the Histidine Switch Model in Influenza Virus Hemagglutinin. BIOPHYSICAL JOURNAL, 104 (2, 1). 68A.

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Abstract

Hemagglutinin is a specific homotrimer glycoprotein on the surface of influenza virus envelope that consists of two subunits, HA1 and HA2. pH-mediated conformational changes of the HA2 chain play a key role in membrane fusion of the viral envelope to the host cell endosomal membrane. Two major steps are involved: first, formation a needle-shaped structure that inserts into the endosomal membrane from the N-terminus; second, re-bending of HA2 at a hinge region (residues 106 to 111) into a hairpin-shaped structure that brings the viral envelope very close to the endosomal membrane, thereby fusion of the two membranes. Following the histidine switch hypothesis, in order to characterize the molecular events taking place in the hinge region of HA2 in response to pH changes, we have performed molecular dynamics (MD) simulation of several hemagglutinin subtypes at neutral and low pH conditions, modeled by changing the protonation state of a histidine side chain located in this region. More than sixty sets of MD simulations (collectively amounting to 20 ms) of a 26-residue representation of the hinge-region were performed in implicit and explicit solvents to study the effects of histidine protonation. Bending of the hinge was observed upon protonation of the histidine in all models with an initial straight conformation, whereas the models with neutral histidine retained their primarily straight conformation. The MD simulations starting from an initially bent conformation resulted in the formation of a straight helical structure upon neutralization of the histidine, while the bent structure was maintained in the presence of a protonated histidine. Finally, mutation of the key histidine to alanine completely abolishes the bending of the peptide altogether. Our results showed that histidine protonation is critical for low-pH conformational changes of the hinge region in HA2.

Item Type: Article
Additional Information: 57th Annual Meeting of the Biophysical-Society, Philadelphia, PA, FEB 02-06, 2013
Subjects: مقالات نمایه شده محققین دانشگاه در سایت ,Web of Science ,Scopus
موارد کلی
Divisions: معاونت تحقیقات و فناوری
Depositing User: GOUMS
Date Deposited: 27 Apr 2015 06:15
Last Modified: 20 Jun 2017 08:12
URI: http://eprints.goums.ac.ir/id/eprint/3814

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