AlphaFold2 Reveals Structural Patterns of Seasonal Haplotype Diversification in SARS-CoV-2 Spike Protein Variants
The slow experimental acquisition of high-quality atomic structures of the rapidly changing proteins of the COVID-19 virus challenges vaccine and therapeutic drug development efforts. Fortunately, deep learning tools such as AlphaFold2 can quickly generate reliable models of atomic structure at expe...
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| Format: | Article |
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MDPI AG
2024-02-01
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| Series: | Biology |
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| Online Access: | https://www.mdpi.com/2079-7737/13/3/134 |
| _version_ | 1827307051914625024 |
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| author | Muhammad Asif Ali Gustavo Caetano-Anollés |
| author_facet | Muhammad Asif Ali Gustavo Caetano-Anollés |
| author_sort | Muhammad Asif Ali |
| collection | DOAJ |
| description | The slow experimental acquisition of high-quality atomic structures of the rapidly changing proteins of the COVID-19 virus challenges vaccine and therapeutic drug development efforts. Fortunately, deep learning tools such as AlphaFold2 can quickly generate reliable models of atomic structure at experimental resolution. Current modeling studies have focused solely on definitions of mutant constellations of Variants of Concern (VOCs), leaving out the impact of haplotypes on protein structure. Here, we conduct a thorough comparative structural analysis of S-proteins belonging to major VOCs and corresponding latitude-delimited haplotypes that affect viral seasonal behavior. Our approach identified molecular regions of importance as well as patterns of structural recruitment. The S1 subunit hosted the majority of structural changes, especially those involving the N-terminal domain (NTD) and the receptor-binding domain (RBD). In particular, structural changes in the NTD were much greater than just translations in three-dimensional space, altering the sub-structures to greater extents. We also revealed a notable pattern of structural recruitment with the early VOCs Alpha and Delta behaving antagonistically by suppressing regions of structural change introduced by their corresponding haplotypes, and the current VOC Omicron behaving synergistically by amplifying or collecting structural change. Remarkably, haplotypes altering the galectin-like structure of the NTD were major contributors to seasonal behavior, supporting its putative environmental-sensing role. Our results provide an extensive view of the evolutionary landscape of the S-protein across the COVID-19 pandemic. This view will help predict important regions of structural change in future variants and haplotypes for more efficient vaccine and drug development. |
| first_indexed | 2024-04-24T18:32:47Z |
| format | Article |
| id | doaj.art-de607c63f1fe440eaae127da3ee9878f |
| institution | Directory Open Access Journal |
| issn | 2079-7737 |
| language | English |
| last_indexed | 2024-04-24T18:32:47Z |
| publishDate | 2024-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biology |
| spelling | doaj.art-de607c63f1fe440eaae127da3ee9878f2024-03-27T13:22:02ZengMDPI AGBiology2079-77372024-02-0113313410.3390/biology13030134AlphaFold2 Reveals Structural Patterns of Seasonal Haplotype Diversification in SARS-CoV-2 Spike Protein VariantsMuhammad Asif Ali0Gustavo Caetano-Anollés1Evolutionary Bioinformatics Laboratory, Department of Crop Sciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USAEvolutionary Bioinformatics Laboratory, Department of Crop Sciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USAThe slow experimental acquisition of high-quality atomic structures of the rapidly changing proteins of the COVID-19 virus challenges vaccine and therapeutic drug development efforts. Fortunately, deep learning tools such as AlphaFold2 can quickly generate reliable models of atomic structure at experimental resolution. Current modeling studies have focused solely on definitions of mutant constellations of Variants of Concern (VOCs), leaving out the impact of haplotypes on protein structure. Here, we conduct a thorough comparative structural analysis of S-proteins belonging to major VOCs and corresponding latitude-delimited haplotypes that affect viral seasonal behavior. Our approach identified molecular regions of importance as well as patterns of structural recruitment. The S1 subunit hosted the majority of structural changes, especially those involving the N-terminal domain (NTD) and the receptor-binding domain (RBD). In particular, structural changes in the NTD were much greater than just translations in three-dimensional space, altering the sub-structures to greater extents. We also revealed a notable pattern of structural recruitment with the early VOCs Alpha and Delta behaving antagonistically by suppressing regions of structural change introduced by their corresponding haplotypes, and the current VOC Omicron behaving synergistically by amplifying or collecting structural change. Remarkably, haplotypes altering the galectin-like structure of the NTD were major contributors to seasonal behavior, supporting its putative environmental-sensing role. Our results provide an extensive view of the evolutionary landscape of the S-protein across the COVID-19 pandemic. This view will help predict important regions of structural change in future variants and haplotypes for more efficient vaccine and drug development.https://www.mdpi.com/2079-7737/13/3/134COVID-19haplotypesvariant of concernAlphaFoldspike proteinmutation |
| spellingShingle | Muhammad Asif Ali Gustavo Caetano-Anollés AlphaFold2 Reveals Structural Patterns of Seasonal Haplotype Diversification in SARS-CoV-2 Spike Protein Variants Biology COVID-19 haplotypes variant of concern AlphaFold spike protein mutation |
| title | AlphaFold2 Reveals Structural Patterns of Seasonal Haplotype Diversification in SARS-CoV-2 Spike Protein Variants |
| title_full | AlphaFold2 Reveals Structural Patterns of Seasonal Haplotype Diversification in SARS-CoV-2 Spike Protein Variants |
| title_fullStr | AlphaFold2 Reveals Structural Patterns of Seasonal Haplotype Diversification in SARS-CoV-2 Spike Protein Variants |
| title_full_unstemmed | AlphaFold2 Reveals Structural Patterns of Seasonal Haplotype Diversification in SARS-CoV-2 Spike Protein Variants |
| title_short | AlphaFold2 Reveals Structural Patterns of Seasonal Haplotype Diversification in SARS-CoV-2 Spike Protein Variants |
| title_sort | alphafold2 reveals structural patterns of seasonal haplotype diversification in sars cov 2 spike protein variants |
| topic | COVID-19 haplotypes variant of concern AlphaFold spike protein mutation |
| url | https://www.mdpi.com/2079-7737/13/3/134 |
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