Dataset Information

Electrostatic energy calculation on the pH-induced conformational change of influenza virus hemagglutinin.

ABSTRACT: The pH-induced conformational change of influenza virus hemagglutinin (HA) has been investigated by calculating the change of electrostatic energy of the fragment of HA2 upon pH change. The average charge and electrostatic free energy are calculated as a function of pH for the fusion peptide (residues 1-20 of HA2) and the polypeptide of residues 54-77 of HA2 by using the finite difference Poisson-Boltzmann method. It is found that as pH decreases from 8 to 5, the electrostatic free energy of the fusogenic state is lowered by approximately 2 kcal/mol and the fusogenic state is less ionized compared to that of the native state for both polypeptides. For the fusion peptide at the fusogenic state, most of ionizable residues are neutral at acidic pH except Glu-11. For the polypeptide of residues 54-77 at the fusogenic state, most of residues except Glu-74 and His-64 are fully charged between pH 5 and pH 8.

SUBMITTER: Choi HS

PROVIDER: S-EPMC1479073 | biostudies-literature | 2006 Jul

REPOSITORIES: biostudies-literature

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Electrostatic energy calculation on the pH-induced conformational change of influenza virus hemagglutinin.

Choi Ho Sup HS Huh June J Jo Won Ho WH

Biophysical journal 20060407 1

The pH-induced conformational change of influenza virus hemagglutinin (HA) has been investigated by calculating the change of electrostatic energy of the fragment of HA2 upon pH change. The average charge and electrostatic free energy are calculated as a function of pH for the fusion peptide (residues 1-20 of HA2) and the polypeptide of residues 54-77 of HA2 by using the finite difference Poisson-Boltzmann method. It is found that as pH decreases from 8 to 5, the electrostatic free energy of the ...[more]

PMID: 16603498

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Project description:The conformational change of the influenza virus hemagglutinin (HA) protein mediating the fusion between the virus envelope and the endosomal membrane was hypothesized to be induced by protonation of specific histidine residues since their pKas match the pHs of late endosomes (pK(a) of ? 6.0). However, such critical key histidine residues remain to be identified. We investigated the highly conserved His184 at the HA1-HA1 interface and His110 at the HA1-HA2 interface of highly pathogenic H5N1 HA as potential pH sensors. By replacing both histidines with different amino acids and analyzing the effect of these mutations on conformational change and fusion, we found that His184, but not His110, plays an essential role in the pH dependence of the conformational change of HA. Computational modeling of the protonated His184 revealed that His184 is central in a conserved interaction network possibly regulating the pH dependence of conformational change via its pKa. As the propensity of histidine to get protonated largely depends on its local environment, mutation of residues in the vicinity of histidine may affect its pK(a). The HA of highly pathogenic H5N1 viruses carries a Glu-to-Arg mutation at position 216 close to His184. By mutation of residue 216 in the highly pathogenic as well as the low pathogenic H5 HA, we observed a significant influence on the pH dependence of conformational change and fusion. These results are in support of a pK(a)-modulating effect of neighboring residues.The main pathogenic determinant of influenza viruses, the hemagglutinin (HA) protein, triggers a key step of the infection process: the fusion of the virus envelope with the endosomal membrane releasing the viral genome. Whereas essential aspects of the fusion-inducing mechanism of HA at low pH are well understood, the molecular trigger of the pH-dependent conformational change inducing fusion has been unclear. We provide evidence that His184 regulates the pH dependence of the HA conformational change via its pK(a). Mutations of neighboring residues which may affect the pK(a) of His184 could play an important role in virus adaptation to a specific host. We suggest that mutation of neighboring residue 216, which is present in all highly pathogenic phenotypes of H5N1 influenza virus strains, contributed to the adaptation of these viruses to the human host via its effect on the pKa of His184.

Dataset Information

Electrostatic energy calculation on the pH-induced conformational change of influenza virus hemagglutinin.

Publications

Electrostatic energy calculation on the pH-induced conformational change of influenza virus hemagglutinin.

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