Allosteric modulation by the fatty acid site in the glycosylated SARS-CoV-2 spike
The spike protein is essential to the SARS-CoV-2 virus life cycle, facilitating virus entry and mediating viral-host membrane fusion. The spike contains a fatty acid (FA) binding site between every two neighbouring receptor-binding domains. This site is coupled to key regions in the protein, but the...
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eLife Sciences Publications Ltd
2025-04-01
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| Online Access: | https://elifesciences.org/articles/97313 |
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| author | A Sofia F Oliveira Fiona L Kearns Mia A Rosenfeld Lorenzo Casalino Lorenzo Tulli Imre Berger Christiane Schaffitzel Andrew D Davidson Rommie E Amaro Adrian J Mulholland |
| author_facet | A Sofia F Oliveira Fiona L Kearns Mia A Rosenfeld Lorenzo Casalino Lorenzo Tulli Imre Berger Christiane Schaffitzel Andrew D Davidson Rommie E Amaro Adrian J Mulholland |
| author_sort | A Sofia F Oliveira |
| collection | DOAJ |
| description | The spike protein is essential to the SARS-CoV-2 virus life cycle, facilitating virus entry and mediating viral-host membrane fusion. The spike contains a fatty acid (FA) binding site between every two neighbouring receptor-binding domains. This site is coupled to key regions in the protein, but the impact of glycans on these allosteric effects has not been investigated. Using dynamical nonequilibrium molecular dynamics (D-NEMD) simulations, we explore the allosteric effects of the FA site in the fully glycosylated spike of the SARS-CoV-2 ancestral variant. Our results identify the allosteric networks connecting the FA site to functionally important regions in the protein, including the receptor-binding motif, an antigenic supersite in the N-terminal domain, the fusion peptide region, and another allosteric site known to bind heme and biliverdin. The networks identified here highlight the complexity of the allosteric modulation in this protein and reveal a striking and unexpected link between different allosteric sites. Comparison of the FA site connections from D-NEMD in the glycosylated and non-glycosylated spike revealed that glycans do not qualitatively change the internal allosteric pathways but can facilitate the transmission of the structural changes within and between subunits. |
| format | Article |
| id | doaj-art-c18f2b71d1054a27959080ea3fcff329 |
| institution | OA Journals |
| issn | 2050-084X |
| language | English |
| publishDate | 2025-04-01 |
| publisher | eLife Sciences Publications Ltd |
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| series | eLife |
| spelling | doaj-art-c18f2b71d1054a27959080ea3fcff3292025-08-20T02:07:24ZengeLife Sciences Publications LtdeLife2050-084X2025-04-011310.7554/eLife.97313Allosteric modulation by the fatty acid site in the glycosylated SARS-CoV-2 spikeA Sofia F Oliveira0https://orcid.org/0000-0001-8753-4950Fiona L Kearns1Mia A Rosenfeld2Lorenzo Casalino3Lorenzo Tulli4https://orcid.org/0009-0008-1268-1217Imre Berger5https://orcid.org/0000-0001-7518-9045Christiane Schaffitzel6https://orcid.org/0000-0002-1516-9760Andrew D Davidson7https://orcid.org/0000-0002-1136-4008Rommie E Amaro8Adrian J Mulholland9https://orcid.org/0000-0003-1015-4567Centre for Computational Chemistry, School of Chemistry, University of Bristol, Bristol, United Kingdom; School of Chemistry, University of Bristol, Bristol, United KingdomDepartment of Chemistry and Biochemistry, University of California San Diego, La Jolla, United StatesDepartment of Chemistry and Biochemistry, University of California San Diego, La Jolla, United StatesDepartment of Chemistry and Biochemistry, University of California San Diego, La Jolla, United StatesCentre for Computational Chemistry, School of Chemistry, University of Bristol, Bristol, United Kingdom; School of Chemistry, University of Bristol, Bristol, United KingdomSchool of Chemistry, University of Bristol, Bristol, United Kingdom; School of Biochemistry, University of Bristol, Bristol, United Kingdom; Max Planck Bristol Centre for Minimal Biology, School of Chemistry, Bristol, United KingdomSchool of Biochemistry, University of Bristol, Bristol, United KingdomSchool of Cellular and Molecular Medicine, University of Bristol, University Walk, Bristol, United KingdomDepartment of Molecular Biology, University of California San Diego, La Jolla, United StatesCentre for Computational Chemistry, School of Chemistry, University of Bristol, Bristol, United Kingdom; School of Chemistry, University of Bristol, Bristol, United KingdomThe spike protein is essential to the SARS-CoV-2 virus life cycle, facilitating virus entry and mediating viral-host membrane fusion. The spike contains a fatty acid (FA) binding site between every two neighbouring receptor-binding domains. This site is coupled to key regions in the protein, but the impact of glycans on these allosteric effects has not been investigated. Using dynamical nonequilibrium molecular dynamics (D-NEMD) simulations, we explore the allosteric effects of the FA site in the fully glycosylated spike of the SARS-CoV-2 ancestral variant. Our results identify the allosteric networks connecting the FA site to functionally important regions in the protein, including the receptor-binding motif, an antigenic supersite in the N-terminal domain, the fusion peptide region, and another allosteric site known to bind heme and biliverdin. The networks identified here highlight the complexity of the allosteric modulation in this protein and reveal a striking and unexpected link between different allosteric sites. Comparison of the FA site connections from D-NEMD in the glycosylated and non-glycosylated spike revealed that glycans do not qualitatively change the internal allosteric pathways but can facilitate the transmission of the structural changes within and between subunits.https://elifesciences.org/articles/97313allosterySARS-CoV-2 spikeglycansnonequilibrium simulationsfatty acids |
| spellingShingle | A Sofia F Oliveira Fiona L Kearns Mia A Rosenfeld Lorenzo Casalino Lorenzo Tulli Imre Berger Christiane Schaffitzel Andrew D Davidson Rommie E Amaro Adrian J Mulholland Allosteric modulation by the fatty acid site in the glycosylated SARS-CoV-2 spike eLife allostery SARS-CoV-2 spike glycans nonequilibrium simulations fatty acids |
| title | Allosteric modulation by the fatty acid site in the glycosylated SARS-CoV-2 spike |
| title_full | Allosteric modulation by the fatty acid site in the glycosylated SARS-CoV-2 spike |
| title_fullStr | Allosteric modulation by the fatty acid site in the glycosylated SARS-CoV-2 spike |
| title_full_unstemmed | Allosteric modulation by the fatty acid site in the glycosylated SARS-CoV-2 spike |
| title_short | Allosteric modulation by the fatty acid site in the glycosylated SARS-CoV-2 spike |
| title_sort | allosteric modulation by the fatty acid site in the glycosylated sars cov 2 spike |
| topic | allostery SARS-CoV-2 spike glycans nonequilibrium simulations fatty acids |
| url | https://elifesciences.org/articles/97313 |
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