The inherent flexibility of receptor binding domains in SARS-CoV-2 spike protein
Spike (S) protein is the primary antigenic target for neutralization and vaccine development for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It decorates the virus surface and undergoes large motions of its receptor binding domains (RBDs) to enter the host cell. Here, we observ...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2022-03-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/75720 |
| _version_ | 1797998540852559872 |
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| author | Hisham M Dokainish Suyong Re Takaharu Mori Chigusa Kobayashi Jaewoon Jung Yuji Sugita |
| author_facet | Hisham M Dokainish Suyong Re Takaharu Mori Chigusa Kobayashi Jaewoon Jung Yuji Sugita |
| author_sort | Hisham M Dokainish |
| collection | DOAJ |
| description | Spike (S) protein is the primary antigenic target for neutralization and vaccine development for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It decorates the virus surface and undergoes large motions of its receptor binding domains (RBDs) to enter the host cell. Here, we observe Down, one-Up, one-Open, and two-Up-like structures in enhanced molecular dynamics simulations, and characterize the transition pathways via inter-domain interactions. Transient salt-bridges between RBDA and RBDC and the interaction with glycan at N343B support RBDA motions from Down to one-Up. Reduced interactions between RBDA and RBDB in one-Up induce RBDB motions toward two-Up. The simulations overall agree with cryo-electron microscopy structure distributions and FRET experiments and provide hidden functional structures, namely, intermediates along Down-to-one-Up transition with druggable cryptic pockets as well as one-Open with a maximum exposed RBD. The inherent flexibility of S-protein thus provides essential information for antiviral drug rational design or vaccine development. |
| first_indexed | 2024-04-11T10:49:20Z |
| format | Article |
| id | doaj.art-e6d2fba80aa44428895594606307f61d |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T10:49:20Z |
| publishDate | 2022-03-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-e6d2fba80aa44428895594606307f61d2022-12-22T04:28:57ZengeLife Sciences Publications LtdeLife2050-084X2022-03-011110.7554/eLife.75720The inherent flexibility of receptor binding domains in SARS-CoV-2 spike proteinHisham M Dokainish0https://orcid.org/0000-0002-4387-4790Suyong Re1https://orcid.org/0000-0002-3752-6554Takaharu Mori2https://orcid.org/0000-0002-8717-2926Chigusa Kobayashi3https://orcid.org/0000-0002-5603-4619Jaewoon Jung4https://orcid.org/0000-0002-2285-4432Yuji Sugita5https://orcid.org/0000-0001-9738-9216Theoretical Molecular Science Laboratory, RIKEN Cluster for Pioneering Research, Wako, JapanArtificial Intelligence Center for Health and Biomedical Research, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan; Laboratory for Biomolecular Function Simulation, RIKEN Center for Biosystems Dynamics Research, Kobe, JapanTheoretical Molecular Science Laboratory, RIKEN Cluster for Pioneering Research, Wako, JapanComputational Biophysics Research Team, RIKEN Center for Computational Science, Kobe, JapanTheoretical Molecular Science Laboratory, RIKEN Cluster for Pioneering Research, Wako, Japan; Computational Biophysics Research Team, RIKEN Center for Computational Science, Kobe, JapanTheoretical Molecular Science Laboratory, RIKEN Cluster for Pioneering Research, Wako, Japan; Laboratory for Biomolecular Function Simulation, RIKEN Center for Biosystems Dynamics Research, Kobe, Japan; Computational Biophysics Research Team, RIKEN Center for Computational Science, Kobe, JapanSpike (S) protein is the primary antigenic target for neutralization and vaccine development for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It decorates the virus surface and undergoes large motions of its receptor binding domains (RBDs) to enter the host cell. Here, we observe Down, one-Up, one-Open, and two-Up-like structures in enhanced molecular dynamics simulations, and characterize the transition pathways via inter-domain interactions. Transient salt-bridges between RBDA and RBDC and the interaction with glycan at N343B support RBDA motions from Down to one-Up. Reduced interactions between RBDA and RBDB in one-Up induce RBDB motions toward two-Up. The simulations overall agree with cryo-electron microscopy structure distributions and FRET experiments and provide hidden functional structures, namely, intermediates along Down-to-one-Up transition with druggable cryptic pockets as well as one-Open with a maximum exposed RBD. The inherent flexibility of S-protein thus provides essential information for antiviral drug rational design or vaccine development.https://elifesciences.org/articles/75720SARS-CoV-2spike proteinconformational transitioncryptic pocketsenhanced sampling |
| spellingShingle | Hisham M Dokainish Suyong Re Takaharu Mori Chigusa Kobayashi Jaewoon Jung Yuji Sugita The inherent flexibility of receptor binding domains in SARS-CoV-2 spike protein eLife SARS-CoV-2 spike protein conformational transition cryptic pockets enhanced sampling |
| title | The inherent flexibility of receptor binding domains in SARS-CoV-2 spike protein |
| title_full | The inherent flexibility of receptor binding domains in SARS-CoV-2 spike protein |
| title_fullStr | The inherent flexibility of receptor binding domains in SARS-CoV-2 spike protein |
| title_full_unstemmed | The inherent flexibility of receptor binding domains in SARS-CoV-2 spike protein |
| title_short | The inherent flexibility of receptor binding domains in SARS-CoV-2 spike protein |
| title_sort | inherent flexibility of receptor binding domains in sars cov 2 spike protein |
| topic | SARS-CoV-2 spike protein conformational transition cryptic pockets enhanced sampling |
| url | https://elifesciences.org/articles/75720 |
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