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Computational Identification of Antibody Epitopes on the Dengue Virus NS1 Protein.

ABSTRACT: We have previously described a method to predict antigenic epitopes on proteins recognized by specific antibodies. Here we have applied this method to identify epitopes on the NS1 proteins of the four Dengue virus serotypes (DENV1-4) that are bound by a small panel of monoclonal antibodies 1H7.4, 1G5.3 and Gus2. Several epitope regions were predicted for these antibodies and these were found to reflect the experimentally observed reactivities. The known binding epitopes on DENV2 for the antibodies 1H7.4 and 1G5.3 were identified, revealing the reasons for the serotype specificity of 1H7.4 and 1G5.3, and the non-selectivity of Gus2. As DENV NS1 is critical for virus replication and a key vaccine candidate, epitope prediction will be valuable in designing appropriate vaccine control strategies. The ability to predict potential epitopes by computational methods significantly reduces the amount of experimental work required to screen peptide libraries for epitope mapping.

SUBMITTER: Jones ML

PROVIDER: S-EPMC6154621 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Computational Identification of Antibody Epitopes on the Dengue Virus NS1 Protein.

Jones Martina L ML Legge Fiona S FS Lebani Kebaneilwe K Mahler Stephen M SM Young Paul R PR Watterson Daniel D Treutlein Herbert R HR Zeng Jun J

Molecules (Basel, Switzerland) 20170410 4

We have previously described a method to predict antigenic epitopes on proteins recognized by specific antibodies. Here we have applied this method to identify epitopes on the NS1 proteins of the four Dengue virus serotypes (DENV1-4) that are bound by a small panel of monoclonal antibodies 1H7.4, 1G5.3 and Gus2. Several epitope regions were predicted for these antibodies and these were found to reflect the experimentally observed reactivities. The known binding epitopes on DENV2 for the antibodi ...[more]

PMID: 28394300

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Project description:The dramatic transformation of the Zika virus (ZIKV) from a relatively unknown virus to a pathogen generating global-wide panic has exposed the dearth of detailed knowledge about this virus. Decades of research in the related Dengue virus (DENV), finally culminating in a vaccine registered for use in endemic regions (CYD-TDV) in three countries, provides key insights in developing strategies for tackling ZIKV, which has caused global panic to microcephaly and Guillain-Barre Syndrome. Dengue virus (DENV), a member of the family Flaviviridae, the causal agent of the self-limiting Dengue fever and the potentially fatal hemorrhagic fever/dengue shock syndrome, has been a scourge in tropical countries for many centuries. The recently solved structure of mature ZIKV (PDB ID:5IRE) has provided key insights into the structure of the envelope (E) and membrane (M) proteins, the primary target of neutralizing antibodies. The previously established MEPP methodology compares two conformations of the same protein and identifies residues with significant spatial and electrostatic perturbations. In the current work, MEPP analyzed the pre-and post-fusion DENV type 2 envelope (E) protein, and identified several known epitopes (His317, Tyr299, Glu26, Arg188, etc.) (MEPPitope). These residues are overwhelmingly conserved in ZIKV and all DENV serotypes, and also enumerates residue pairs that undergo significant polarity reversal. Characterization of α-helices in E-proteins show that α1 is not conserved in the sequence space of ZIKV and DENV. Furthermore, perturbation of α1 in the post-fusion DENV structure includes a known epitope Asp215, a residue absent in the pre-fusion α1. A cationic β-sheet in the GAG-binding domain that is stereochemically equivalent in ZIKV and all DENV serotypes is also highlighted due to a residue pair (Arg286-Arg288) that has a significant electrostatic polarity reversal upon fusion. Finally, two highly conserved residues (Thr32 and Thr40), with little emphasis in existing literature, are found to have significant electrostatic perturbation. Thus, a combination of different computational methods enable the rapid and rational detection of critical residues as epitopes in the search for an elusive therapy or vaccine that neutralizes multiple members of the Flaviviridae family. These secondary structures are conserved in the related Dengue virus (DENV), and possibly rationalize isolation techniques particle adsorption on magnetic beads coated with anionic polymers and anionic antiviral agents (viprolaxikine) for DENV. These amphipathic α-helices could enable design of molecules for inhibiting α-helix mediated protein-protein interactions. Finally, comparison of these secondary structures in proteins from related families illuminate subtle changes in the proteins that might render them ineffective to previously successful drugs and vaccines, which are difficult to identify by a simple sequence or structural alignment. Finally, conflicting results about residues that are involved in neutralizing a DENV-E protein by the potent antibody 5J7 (PDB ID:3J6U) are reported.

Dataset Information

Computational Identification of Antibody Epitopes on the Dengue Virus NS1 Protein.

Publications

Computational Identification of Antibody Epitopes on the Dengue Virus NS1 Protein.

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