Allosteric modulation by the fatty acid site in the glycosylated SARS-CoV-2 spike DOI Creative Commons
A. Sofia F. Oliveira, Fiona L. Kearns, Mia A. Rosenfeld

et al.

eLife, Journal Year: 2024, Volume and Issue: unknown

Published: July 24, 2024

The spike protein is essential to the SARS-CoV-2 virus life cycle, facilitating entry and mediating viral-host membrane fusion. contains a fatty acid (FA) binding site between every two neighbouring receptor-binding domains. This coupled key regions in protein, but impact of glycans on these allosteric effects has not been investigated. Using dynamical nonequilibrium molecular dynamics (D-NEMD) simulations, we explore FA fully glycosylated ancestral variant. Our results identify networks connecting functionally important including motif, an antigenic supersite N-terminal domain, fusion peptide region, another known bind heme biliverdin. identified here highlight complexity modulation this reveal striking unexpected link different sites. Comparison connections from D-NEMD non-glycosylated revealed that do qualitatively change internal pathways can facilitate transmission structural changes within subunits.

Language: Английский

Identification and Understanding of Allostery Hotspots in Proteins: Integration of Deep Mutational Scanning and Multi-faceted Computational Analyses DOI
Qiang Cui

Journal of Molecular Biology, Journal Year: 2025, Volume and Issue: unknown, P. 168998 - 168998

Published: Feb. 1, 2025

Language: Английский

Citations

0
Allosteric modulation by the fatty acid site in the glycosylated SARS-CoV-2 spike DOI Open Access
A. Sofia F. Oliveira, Fiona L. Kearns, Mia A. Rosenfeld

et al.

Published: March 11, 2025

The trimeric spike protein plays an essential role in the SARS-CoV-2 virus lifecycle, facilitating entry through binding to cellular receptor angiotensin-converting enzyme 2 (ACE2) and mediating viral-host membrane fusion. contains a fatty acid (FA) site at interface between two neighbouring receptor-binding domains. This site, also found some other coronaviruses, binds free acids such as linoleic acid. Binding this locks non-infectious, closed conformation. is coupled functionally important regions, but effects of glycans on these allosteric have not been investigated. Understanding allostery how modulates behaviour could potentiate development promising alternative strategies for new coronavirus therapies. Here, we apply dynamical nonequilibrium molecular dynamics (D-NEMD) simulations investigate FA fully glycosylated original ancestral variant. results show networks that connect functional regions protein, including more than 40 Å away, motif, antigenic supersite N-terminal domain, furin cleavage surrounding fusion peptide, another known bind heme biliverdin. identified here highlight complexity modulation reveal striking unexpected connection different sites. Notably, 65% amino substitutions, deletions insertions Alpha, Beta, Delta, Gamma Omicron variants map onto or close pathways. Comparison connections from D-NEMD non-glycosylated spikes revealed presence does qualitatively change internal pathways within with transmission structural changes subunits.

Language: Английский

Citations

0
A Reflection on the Use of Molecular Simulation to Respond to SARS-CoV-2 Pandemic Threats DOI Creative Commons
Lorenzo Casalino, Carlos A. Ramos‐Guzmán, Rommie E. Amaro

et al.

The Journal of Physical Chemistry Letters, Journal Year: 2025, Volume and Issue: unknown, P. 3249 - 3263

Published: March 21, 2025

Molecular simulations play important roles in understanding the lifecycle of SARS-CoV-2 virus and contribute to design development antiviral agents diagnostic tests for COVID. Here, we discuss insights that such have provided challenges involved, focusing on main protease (Mpro) spike glycoprotein. Mpro is leading target antivirals, while glycoprotein vaccine design. Finally, reflect lessons from this pandemic simulation community. Data sharing initiatives collaborations across international research community contributed advancing knowledge should be built help future pandemics other global as antimicrobial resistance.

Language: Английский

Citations

0
Allosteric modulation by the fatty acid site in the glycosylated SARS-CoV-2 spike DOI Creative Commons
A. Sofia F. Oliveira, Fiona L. Kearns, Mia A. Rosenfeld

et al.

eLife, Journal Year: 2025, Volume and Issue: 13

Published: April 10, 2025

The spike protein is essential to the SARS-CoV-2 virus life cycle, facilitating entry and mediating viral-host membrane fusion. contains a fatty acid (FA) binding site between every two neighbouring receptor-binding domains. This coupled key regions in protein, but impact of glycans on these allosteric effects has not been investigated. Using dynamical nonequilibrium molecular dynamics (D-NEMD) simulations, we explore FA fully glycosylated ancestral variant. Our results identify networks connecting functionally important including motif, an antigenic supersite N-terminal domain, fusion peptide region, another known bind heme biliverdin. identified here highlight complexity modulation this reveal striking unexpected link different sites. Comparison connections from D-NEMD non-glycosylated revealed that do qualitatively change internal pathways can facilitate transmission structural changes within subunits.

Language: Английский

Citations

0
Allosteric modulation by the fatty acid site in the glycosylated SARS-CoV-2 spike DOI Creative Commons
A. Sofia F. Oliveira, Fiona L. Kearns, Mia A. Rosenfeld

et al.

eLife, Journal Year: 2024, Volume and Issue: unknown

Published: July 24, 2024

The spike protein is essential to the SARS-CoV-2 virus life cycle, facilitating entry and mediating viral-host membrane fusion. contains a fatty acid (FA) binding site between every two neighbouring receptor-binding domains. This coupled key regions in protein, but impact of glycans on these allosteric effects has not been investigated. Using dynamical nonequilibrium molecular dynamics (D-NEMD) simulations, we explore FA fully glycosylated ancestral variant. Our results identify networks connecting functionally important including motif, an antigenic supersite N-terminal domain, fusion peptide region, another known bind heme biliverdin. identified here highlight complexity modulation this reveal striking unexpected link different sites. Comparison connections from D-NEMD non-glycosylated revealed that do qualitatively change internal pathways can facilitate transmission structural changes within subunits.

Language: Английский

Citations

1