title: The pH dependence of flavivirus envelope protein structure: insights from molecular dynamics simulations.
abstract: The flavivirus membrane fusion is triggered by the acid pH of the endosomes after virus endocytosis. The proposed mechanism involves changes in the protonation state of conserved histidine residues of the E protein present in the viral surface that undergoes a series of structural rearrangements that result in the fusion between the endosome and viral bilayers. We studied the pH dependence of E protein rearrangements of dengue virus type 2, used as a model, in the pH range experimented by the virus along the fusion process. We employed a low computational cost scheme to explore the behavior of the E protein by molecular dynamics (MD) simulations of complete systems that include the protein, the solvent, and ions. The procedure alternates cyclically the update of the ionization states of the protein residues with common MD steps applied to the new ionization configuration. Important pH-dependent protein structure rearrangements consistent with the changes of the protonation states of conserved histidine residues were observed. The involvement of other conserved residues in the flavivirus in the rearrangements was also identified. The results show interesting correlations with a proposed model for the fusion mechanism, as well as the experimentally identified key residues, contributing to a better understanding of the structural changes in protein E that lead to the fusion process.
authors: a Grupo de Simulação Molecular, Departamento de Química, Faculdade de Filosofia Ciências e Letras de Ribeirão Preto, Universidade de São Paulo , Ribeirão Preto-SP , Brazil .
authors: Carlos Alessandro
authors: CA
authors: Fuzo
authors: Léo
authors: L
authors: Degrève
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D017124:Conserved Sequence; D005416:Flavivirus / Q000737:chemistry*; D006639:Histidine / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D056004:Molecular Dynamics Simulation; D017434:Protein Structure, Tertiary; D011522:Protons; D013997:Time Factors; D014759:Viral Envelope Proteins / Q000737:chemistry*
chemical_list: D000596:Amino Acids; D011522:Protons; D014759:Viral Envelope Proteins; D006639:Histidine
keywords: dengue virus; flavivirus; histidine protonation; molecular dynamics of envelope protein; pH-dependent protein rearrangements