A pH-dependent cluster of charges in a conserved cryptic pocket on flaviviral envelopes
Flaviviruses are enveloped viruses which include human pathogens that are predominantly transmitted by mosquitoes and ticks. Some, such as dengue virus, exhibit the phenomenon of antibody-dependent enhancement (ADE) of disease, making vaccine-based routes of fighting infections problematic. The pH-d...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2023-05-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/82447 |
| _version_ | 1797832881316298752 |
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| author | Lorena Zuzic Jan K Marzinek Ganesh S Anand Jim Warwicker Peter J Bond |
| author_facet | Lorena Zuzic Jan K Marzinek Ganesh S Anand Jim Warwicker Peter J Bond |
| author_sort | Lorena Zuzic |
| collection | DOAJ |
| description | Flaviviruses are enveloped viruses which include human pathogens that are predominantly transmitted by mosquitoes and ticks. Some, such as dengue virus, exhibit the phenomenon of antibody-dependent enhancement (ADE) of disease, making vaccine-based routes of fighting infections problematic. The pH-dependent conformational change of the envelope (E) protein required for fusion between the viral and endosomal membranes is an attractive point of inhibition by antivirals as it has the potential to diminish the effects of ADE. We examined six flaviviruses by employing large-scale molecular dynamics (MD) simulations of raft systems that represent a substantial portion of the flaviviral envelope. We utilised a benzene-mapping approach that led to a discovery of shared hotspots and conserved cryptic sites. A cryptic pocket previously shown to bind a detergent molecule exhibited strain-specific characteristics. An alternative conserved cryptic site at the E protein domain interfaces showed a consistent dynamic behaviour across flaviviruses and contained a conserved cluster of ionisable residues. Constant-pH simulations revealed cluster and domain-interface disruption under low pH conditions. Based on this, we propose a cluster-dependent mechanism that addresses inconsistencies in the histidine-switch hypothesis and highlights the role of cluster protonation in orchestrating the domain dissociation pivotal for the formation of the fusogenic trimer. |
| first_indexed | 2024-04-09T14:14:49Z |
| format | Article |
| id | doaj.art-0b6f1b40f7e8491f968e488d8663219f |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-09T14:14:49Z |
| publishDate | 2023-05-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-0b6f1b40f7e8491f968e488d8663219f2023-05-05T12:06:16ZengeLife Sciences Publications LtdeLife2050-084X2023-05-011210.7554/eLife.82447A pH-dependent cluster of charges in a conserved cryptic pocket on flaviviral envelopesLorena Zuzic0https://orcid.org/0000-0002-7834-612XJan K Marzinek1https://orcid.org/0000-0002-5493-8753Ganesh S Anand2https://orcid.org/0000-0001-8995-3067Jim Warwicker3Peter J Bond4https://orcid.org/0000-0003-2900-098XBioinformatics Institute (A*STAR), Singapore, Singapore; Department of Chemistry, Manchester Institute of Biotechnology, The University of Manchester, Manchester, United KingdomBioinformatics Institute (A*STAR), Singapore, SingaporeDepartment of Biological Sciences, 16 Science Drive 4, National University of Singapore, Singapore, Singapore; Department of Chemistry, The Pennsylvania State University, University Park, United StatesSchool of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Institute of Biotechnology, The University of Manchester, Manchester, United KingdomBioinformatics Institute (A*STAR), Singapore, Singapore; Department of Biological Sciences, 16 Science Drive 4, National University of Singapore, Singapore, SingaporeFlaviviruses are enveloped viruses which include human pathogens that are predominantly transmitted by mosquitoes and ticks. Some, such as dengue virus, exhibit the phenomenon of antibody-dependent enhancement (ADE) of disease, making vaccine-based routes of fighting infections problematic. The pH-dependent conformational change of the envelope (E) protein required for fusion between the viral and endosomal membranes is an attractive point of inhibition by antivirals as it has the potential to diminish the effects of ADE. We examined six flaviviruses by employing large-scale molecular dynamics (MD) simulations of raft systems that represent a substantial portion of the flaviviral envelope. We utilised a benzene-mapping approach that led to a discovery of shared hotspots and conserved cryptic sites. A cryptic pocket previously shown to bind a detergent molecule exhibited strain-specific characteristics. An alternative conserved cryptic site at the E protein domain interfaces showed a consistent dynamic behaviour across flaviviruses and contained a conserved cluster of ionisable residues. Constant-pH simulations revealed cluster and domain-interface disruption under low pH conditions. Based on this, we propose a cluster-dependent mechanism that addresses inconsistencies in the histidine-switch hypothesis and highlights the role of cluster protonation in orchestrating the domain dissociation pivotal for the formation of the fusogenic trimer.https://elifesciences.org/articles/82447flavivirusenveloped virusbenzene-mappingcryptic pocketsconstant-pH simulationsmolecular dynamics simulations |
| spellingShingle | Lorena Zuzic Jan K Marzinek Ganesh S Anand Jim Warwicker Peter J Bond A pH-dependent cluster of charges in a conserved cryptic pocket on flaviviral envelopes eLife flavivirus enveloped virus benzene-mapping cryptic pockets constant-pH simulations molecular dynamics simulations |
| title | A pH-dependent cluster of charges in a conserved cryptic pocket on flaviviral envelopes |
| title_full | A pH-dependent cluster of charges in a conserved cryptic pocket on flaviviral envelopes |
| title_fullStr | A pH-dependent cluster of charges in a conserved cryptic pocket on flaviviral envelopes |
| title_full_unstemmed | A pH-dependent cluster of charges in a conserved cryptic pocket on flaviviral envelopes |
| title_short | A pH-dependent cluster of charges in a conserved cryptic pocket on flaviviral envelopes |
| title_sort | ph dependent cluster of charges in a conserved cryptic pocket on flaviviral envelopes |
| topic | flavivirus enveloped virus benzene-mapping cryptic pockets constant-pH simulations molecular dynamics simulations |
| url | https://elifesciences.org/articles/82447 |
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