Structural insights into the effect of mutations in the spike protein of SARS-CoV-2 on the binding with human furin protein
The SARS COV-2 and its variants are spreading around the world at an alarming speed, due to its higher transmissibility and the conformational changes caused by mutations. The resulting COVID-19 pandemic has imposed severe health consequences on human health. Several countries of the world including...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-04-01
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| Series: | Heliyon |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2405844023022909 |
| _version_ | 1797836948031668224 |
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| author | Muhammad Suleman Muhammad Luqman Dong-Qing Wei Shahid Ali Syed Shujait Ali Abbas Khan Haji Khan Zafar Ali Wajid Khan Muhammad Rizwan Naeem Ullah |
| author_facet | Muhammad Suleman Muhammad Luqman Dong-Qing Wei Shahid Ali Syed Shujait Ali Abbas Khan Haji Khan Zafar Ali Wajid Khan Muhammad Rizwan Naeem Ullah |
| author_sort | Muhammad Suleman |
| collection | DOAJ |
| description | The SARS COV-2 and its variants are spreading around the world at an alarming speed, due to its higher transmissibility and the conformational changes caused by mutations. The resulting COVID-19 pandemic has imposed severe health consequences on human health. Several countries of the world including Pakistan have studied its genome extensively and provided productive findings. In the current study, the mCSM, DynaMut2, and I-Mutant servers were used to analyze the effect of identified mutations on the structural stability of spike protein however, the molecular docking and simulations approaches were used to evaluate the dynamics of the bonding network between the wild-type and mutant spike proteins with furin. We addressed the mutational modifications that have occurred in the spike protein of SARS-COV-2 that were found in 215 Pakistani's isolates of COVID-19 patients to study the influence of mutations on the stability of the protein and its interaction with the host cell. We found 7 single amino acid substitute mutations in various domains that reside in spike protein. The H49Y, N74K, G181V, and G446V were found in the S1 domain while the D614A, V622F, and Q677H mutations were found in the central helices of the spike protein. Based on the observation, G181V, G446V, D614A, and V622F mutants were found highly destabilizing and responsible for structural perturbation. Protein-protein docking and molecular simulation analysis with that of furin have predicted that all the mutants enhanced the binding efficiency however, the V622F mutant has greatly altered the binding capacity which is further verified by the KD value (7.1 E−14) and therefore may enhance the spike protein cleavage by Furin and increase the rate of infectivity by SARS-CoV-2. On the other hand, the total binding energy for each complex was calculated which revealed −50.57 kcal/mol for the wild type, for G181V −52.69 kcal/mol, for G446V −56.44 kcal/mol, for D614A −59.78 kcal/mol while for V622F the TBE was calculated to be −85.84 kcal/mol. Overall, the current finding shows that these mutations have increased the binding of Furin for spike protein and shows that D614A and V622F have significant effects on the binding and infectivity. |
| first_indexed | 2024-04-09T15:18:11Z |
| format | Article |
| id | doaj.art-59664881388749c3a83ec63d6792680f |
| institution | Directory Open Access Journal |
| issn | 2405-8440 |
| language | English |
| last_indexed | 2024-04-09T15:18:11Z |
| publishDate | 2023-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Heliyon |
| spelling | doaj.art-59664881388749c3a83ec63d6792680f2023-04-29T14:55:13ZengElsevierHeliyon2405-84402023-04-0194e15083Structural insights into the effect of mutations in the spike protein of SARS-CoV-2 on the binding with human furin proteinMuhammad Suleman0Muhammad Luqman1Dong-Qing Wei2Shahid Ali3Syed Shujait Ali4Abbas Khan5Haji Khan6Zafar Ali7Wajid Khan8Muhammad Rizwan9Naeem Ullah10Center for Biotechnology and Microbiology, University of Swat, Swat, Pakistan; Corresponding author.Center for Biotechnology and Microbiology, University of Swat, Swat, PakistanCenter for Biotechnology and Microbiology, University of Swat, Swat, Pakistan; Department of Bioinformatics and Biological Statistics, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200240, PR ChinaCenter for Biotechnology and Microbiology, University of Swat, Swat, PakistanCenter for Biotechnology and Microbiology, University of Swat, Swat, PakistanDepartment of Bioinformatics and Biological Statistics, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200240, PR ChinaCenter for Biotechnology and Microbiology, University of Swat, Swat, PakistanCenter for Biotechnology and Microbiology, University of Swat, Swat, PakistanCenter for Biotechnology and Microbiology, University of Swat, Swat, PakistanCenter for Biotechnology and Microbiology, University of Swat, Swat, PakistanDepartment of Computer and Software Technology, University of Swat, Swat, PakistanThe SARS COV-2 and its variants are spreading around the world at an alarming speed, due to its higher transmissibility and the conformational changes caused by mutations. The resulting COVID-19 pandemic has imposed severe health consequences on human health. Several countries of the world including Pakistan have studied its genome extensively and provided productive findings. In the current study, the mCSM, DynaMut2, and I-Mutant servers were used to analyze the effect of identified mutations on the structural stability of spike protein however, the molecular docking and simulations approaches were used to evaluate the dynamics of the bonding network between the wild-type and mutant spike proteins with furin. We addressed the mutational modifications that have occurred in the spike protein of SARS-COV-2 that were found in 215 Pakistani's isolates of COVID-19 patients to study the influence of mutations on the stability of the protein and its interaction with the host cell. We found 7 single amino acid substitute mutations in various domains that reside in spike protein. The H49Y, N74K, G181V, and G446V were found in the S1 domain while the D614A, V622F, and Q677H mutations were found in the central helices of the spike protein. Based on the observation, G181V, G446V, D614A, and V622F mutants were found highly destabilizing and responsible for structural perturbation. Protein-protein docking and molecular simulation analysis with that of furin have predicted that all the mutants enhanced the binding efficiency however, the V622F mutant has greatly altered the binding capacity which is further verified by the KD value (7.1 E−14) and therefore may enhance the spike protein cleavage by Furin and increase the rate of infectivity by SARS-CoV-2. On the other hand, the total binding energy for each complex was calculated which revealed −50.57 kcal/mol for the wild type, for G181V −52.69 kcal/mol, for G446V −56.44 kcal/mol, for D614A −59.78 kcal/mol while for V622F the TBE was calculated to be −85.84 kcal/mol. Overall, the current finding shows that these mutations have increased the binding of Furin for spike protein and shows that D614A and V622F have significant effects on the binding and infectivity.http://www.sciencedirect.com/science/article/pii/S2405844023022909SARS COV-2FurinMolecular dockingMolecular simulationS-ProteinMutation |
| spellingShingle | Muhammad Suleman Muhammad Luqman Dong-Qing Wei Shahid Ali Syed Shujait Ali Abbas Khan Haji Khan Zafar Ali Wajid Khan Muhammad Rizwan Naeem Ullah Structural insights into the effect of mutations in the spike protein of SARS-CoV-2 on the binding with human furin protein Heliyon SARS COV-2 Furin Molecular docking Molecular simulation S-Protein Mutation |
| title | Structural insights into the effect of mutations in the spike protein of SARS-CoV-2 on the binding with human furin protein |
| title_full | Structural insights into the effect of mutations in the spike protein of SARS-CoV-2 on the binding with human furin protein |
| title_fullStr | Structural insights into the effect of mutations in the spike protein of SARS-CoV-2 on the binding with human furin protein |
| title_full_unstemmed | Structural insights into the effect of mutations in the spike protein of SARS-CoV-2 on the binding with human furin protein |
| title_short | Structural insights into the effect of mutations in the spike protein of SARS-CoV-2 on the binding with human furin protein |
| title_sort | structural insights into the effect of mutations in the spike protein of sars cov 2 on the binding with human furin protein |
| topic | SARS COV-2 Furin Molecular docking Molecular simulation S-Protein Mutation |
| url | http://www.sciencedirect.com/science/article/pii/S2405844023022909 |
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