Abstract
Introduction: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) affects the lower respiratory tract by binding to angiotensin-converting enzyme 2 (ACE2) via its S-protein.
Recent emerging SARS-CoV-2 variants from the United Kingdom (B.1.1.7) and South Africa (501Y.V2) are spreading worldwide at an alarming rate. The new variants have manifested amino acid substitution K417N, E484K, and N501Y on the RBD domain that binds to ACE2. These mutations may influence the binding of the S-protein to ACE2 and affect viral entry into the host cell.
Methods: In this study, we modelled the amino acid substitutions on the S-protein and utilised the HADDOCK server to assess the S-protein RBD domain binding with ACE2. Additionally, we calculated the binding affinity of ACE2 to S-protein WT, B.1.1.7 and 501Y.V2 variants using Molecular Mechanics-Generalized Born Surface Area (MM/GBSA).
Results: We demonstrated that the S-protein of both variants possesses a higher binding affinity to ACE2 than WT, with the South African 501Y.V2 being more infective than the B.1.1.7 that originated in the United Kingdom.
Conclusion: The South African 501Y.V2 variant presents three amino acid substitutions that changed the H-bonding network, resulting in a higher affinity to ACE2, indicating that the 501Y.V2 strain is more infective than the B.1.1.7 strain.
Keywords: SARS-CoV-2, protein-protein docking, angiotensin-converting enzyme 2 (ACE2), S-protein, WT-RBD docking, lysina.
[1]
Wang, C.; Horby, P.W.; Hayden, F.G.; Gao, G.F. A novel coronavirus outbreak of global health concern. Lancet, 2020, 395(10223), 470-473.
[http://dx.doi.org/10.1016/S0140-6736(20)30185-9] [PMID: 31986257]
[http://dx.doi.org/10.1016/S0140-6736(20)30185-9] [PMID: 31986257]
[2]
Zhu, N.; Zhang, D.; Wang, W.; Li, X.; Yang, B.; Song, J.; Zhao, X.; Huang, B.; Shi, W.; Lu, R.; Niu, P.; Zhan, F.; Ma, X.; Wang, D.; Xu, W.; Wu, G.; Gao, G.F.; Tan, W. A novel coronavirus from patients with pneumonia in China, 2019. N. Engl. J. Med., 2020, 382, 727-733.
[http://dx.doi.org/10.1056/NEJMoa2001017] [PMID: 31978945]
[http://dx.doi.org/10.1056/NEJMoa2001017] [PMID: 31978945]
[3]
Gordon, D.E.; Jang, G.M.; Bouhaddou, M.; Xu, J.; Obernier, K.; White, K.M.; O’Meara, M.J.; Rezelj, V.V.; Guo, J.Z.; Swaney, D.L.; Tummino, T.A.; Hüttenhain, R.; Kaake, R.M.; Richards, A.L.; Tutuncuoglu, B.; Foussard, H.; Batra, J.; Haas, K.; Modak, M.; Kim, M.; Haas, P.; Polacco, B.J.; Braberg, H.; Fabius, J.M.; Eckhardt, M.; Soucheray, M.; Bennett, M.J.; Cakir, M.; McGregor, M.J.; Li, Q.; Meyer, B.; Roesch, F.; Vallet, T.; Mac Kain, A.; Miorin, L.; Moreno, E.; Naing, Z.Z.C.; Zhou, Y.; Peng, S.; Shi, Y.; Zhang, Z.; Shen, W.; Kirby, I.T.; Melnyk, J.E.; Chorba, J.S.; Lou, K.; Dai, S.A.; Barrio-Hernandez, I.; Memon, D.; Hernandez-Armenta, C.; Lyu, J.; Mathy, C.J.P.; Peri-ca, T.; Pilla, K.B.; Ganesan, S.J.; Saltzberg, D.J.; Rakesh, R.; Liu, X.; Rosenthal, S.B.; Calviello, L.; Venkataramanan, S.; Liboy-Lugo, J.; Lin, Y.; Huang, X.P.; Liu, Y.; Wankowicz, S.A.; Bohn, M.; Safari, M.; Ugur, F.S.; Koh, C.; Savar, N.S.; Tran, Q.D.; Shengjuler, D.; Fletch-er, S.J.; O’Neal, M.C.; Cai, Y.; Chang, J.C.J.; Broadhurst, D.J.; Klippsten, S.; Sharp, P.P.; Wenzell, N.A.; Kuzuoglu-Ozturk, D.; Wang, H.Y.; Trenker, R.; Young, J.M.; Cavero, D.A.; Hiatt, J.; Roth, T.L.; Rathore, U.; Subramanian, A.; Noack, J.; Hubert, M.; Stroud, R.M.; Frankel, A.D.; Rosenberg, O.S.; Verba, K.A.; Agard, D.A.; Ott, M.; Emerman, M.; Jura, N.; von Zastrow, M.; Verdin, E.; Ashworth, A.; Schwartz, O.; d’Enfert, C.; Mukherjee, S.; Jacobson, M.; Malik, H.S.; Fujimori, D.G.; Ideker, T.; Craik, C.S.; Floor, S.N.; Fraser, J.S.; Gross, J.D.; Sali, A.; Roth, B.L.; Ruggero, D.; Taunton, J.; Kortemme, T.; Beltrao, P.; Vignuzzi, M.; García-Sastre, A.; Shokat, K.M.; Shoichet, B.K.; Krogan, N.J.A. SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature, 2020, 583(7816), 459-468.
[http://dx.doi.org/10.1038/s41586-020-2286-9] [PMID: 32353859]
[http://dx.doi.org/10.1038/s41586-020-2286-9] [PMID: 32353859]
[4]
Yan, T.; Xiao, R.; Lin, G. Angiotensin-converting enzyme 2 in severe acute respiratory syndrome coronavirus and SARS-CoV-2: A dou-ble-edged sword? FASEB J., 2020, 34(5), 6017-6026.
[http://dx.doi.org/10.1096/fj.202000782] [PMID: 32306452]
[http://dx.doi.org/10.1096/fj.202000782] [PMID: 32306452]
[5]
Bosso, M.; Thanaraj, T.A.; Abu-Farha, M.; Alanbaei, M.; Abubaker, J.; Al-Mulla, F. The two faces of ACE2: the role of ACE2 receptor and its polymorphisms in hypertension and COVID-19. Mol. Ther. Methods Clin. Dev., 2020, 18, 321-327.
[http://dx.doi.org/10.1016/j.omtm.2020.06.017] [PMID: 32665962]
[http://dx.doi.org/10.1016/j.omtm.2020.06.017] [PMID: 32665962]
[6]
Cai, Y.; Zhang, J.; Xiao, T.; Peng, H.; Sterling, S.M.; Walsh, R.M., Jr; Rawson, S.; Rits-Volloch, S.; Chen, B. Distinct conformational states of SARS-CoV-2 spike protein. Science, 2020, 369(6511), 1586-1592.
[http://dx.doi.org/10.1126/science.abd4251] [PMID: 32694201]
[http://dx.doi.org/10.1126/science.abd4251] [PMID: 32694201]
[7]
Yan, R.; Zhang, Y.; Li, Y.; Xia, L.; Guo, Y.; Zhou, Q. Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. Science, 2020, 367(6485), 1444-1448.
[http://dx.doi.org/10.1126/science.abb2762] [PMID: 32132184]
[http://dx.doi.org/10.1126/science.abb2762] [PMID: 32132184]
[8]
Luan, J.; Lu, Y.; Jin, X.; Zhang, L. Spike protein recognition of mammalian ACE2 predicts the host range and an optimized ACE2 for SARS-CoV-2 infection. Biochem. Biophys. Res. Commun., 2020, 526(1), 165-169.
[http://dx.doi.org/10.1016/j.bbrc.2020.03.047] [PMID: 32201080]
[http://dx.doi.org/10.1016/j.bbrc.2020.03.047] [PMID: 32201080]
[9]
García-Iriepa, C.; Hognon, C.; Francés-Monerris, A.; Iriepa, I.; Miclot, T.; Barone, G.; Monari, A.; Marazzi, M. Thermodynamics of the interaction between the spike protein of severe acute respiratory syndrome coronavirus-2 and the receptor of human angiotensin-converting enzyme 2. effects of possible ligands. J. Phys. Chem. Lett., 2020, 11(21), 9272-9281.
[http://dx.doi.org/10.1021/acs.jpclett.0c02203] [PMID: 33085491]
[http://dx.doi.org/10.1021/acs.jpclett.0c02203] [PMID: 33085491]
[10]
Leung, K.; Shum, M.H.; Leung, G.M.; Lam, T.T.; Wu, J.T. Early transmissibility assessment of the N501Y mutant strains of SARS-CoV-2 in the United Kingdom, october to november 2020. Euro Surveill., 2021, 26(1), 2002106.
[http://dx.doi.org/10.2807/1560-7917.ES.2020.26.1.2002106] [PMID: 33413740]
[http://dx.doi.org/10.2807/1560-7917.ES.2020.26.1.2002106] [PMID: 33413740]
[11]
Tegally, H.; Wilkinson, E.; Giovanetti, M.; Iranzadeh, A.; Fonseca, V.; Giandhari, J.; Doolabh, D.; Pillay, S.; San, E.J.; Msomi, N. Emer-gence and rapid spread of a new severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) lineage with multiple spike mu-tations in South Africa. medRxiv, 2020.
[http://dx.doi.org/10.1101/2020.12.21.20248640]
[http://dx.doi.org/10.1101/2020.12.21.20248640]
[12]
Mohammad, A.; Alshawaf, E.; Marafie, S.K.; Abu-Farha, M.; Abubaker, J.; Al-Mulla, F. Higher binding affinity of furin to SARS-CoV-2 spike (S) protein D614G could be associated with higher SARS-CoV-2 infectivity. Int. J. Infect. Dis., 2020, 103, 611-616.
[PMID: 33075532]
[PMID: 33075532]
[13]
Eaaswarkhanth, M.; Al Madhoun, A.; Al-Mulla, F. Could the D614G substitution in the SARS-CoV-2 spike (S) protein be associated with higher COVID-19 mortality? Int. J. Infect. Dis., 2020, 96, 459-460.
[http://dx.doi.org/10.1016/j.ijid.2020.05.071] [PMID: 32464271]
[http://dx.doi.org/10.1016/j.ijid.2020.05.071] [PMID: 32464271]
[14]
Phan, T. Genetic diversity and evolution of SARS-CoV-2. Infect. Genet. Evol., 2020, 81, 104260.
[http://dx.doi.org/10.1016/j.meegid.2020.104260] [PMID: 32092483]
[http://dx.doi.org/10.1016/j.meegid.2020.104260] [PMID: 32092483]
[15]
Kollman, P.A.; Massova, I.; Reyes, C.; Kuhn, B.; Huo, S.; Chong, L.; Lee, M.; Lee, T.; Duan, Y.; Wang, W.; Donini, O.; Cieplak, P.; Srini-vasan, J.; Case, D.A.; Cheatham, T.E., III Calculating structures and free energies of complex molecules: combining molecular mechanics and continuum models. Acc. Chem. Res., 2000, 33(12), 889-897.
[http://dx.doi.org/10.1021/ar000033j] [PMID: 11123888]
[http://dx.doi.org/10.1021/ar000033j] [PMID: 11123888]
[16]
Wrapp, D.; Wang, N.; Corbett, K.S.; Goldsmith, J.A.; Hsieh, C.L.; Abiona, O.; Graham, B.S.; McLellan, J.S. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science, 2020, 367(6483), 1260-1263.
[http://dx.doi.org/10.1126/science.abb2507] [PMID: 32075877]
[http://dx.doi.org/10.1126/science.abb2507] [PMID: 32075877]
[17]
Waterhouse, A.; Bertoni, M.; Bienert, S.; Studer, G.; Tauriello, G.; Gumienny, R.; Heer, F.T.; de Beer, T.A.P.; Rempfer, C.; Bordoli, L.; Lepore, R.; Schwede, T. SWISS-MODEL: homology modelling of protein structures and complexes. Nucleic Acids Res., 2018, 46(W1), W296-W303.
[http://dx.doi.org/10.1093/nar/gky427] [PMID: 29788355]
[http://dx.doi.org/10.1093/nar/gky427] [PMID: 29788355]
[18]
Rodrigues, C.H.; Pires, D.E.; Ascher, D.B. DynaMut: predicting the impact of mutations on protein conformation, flexibility and stability. Nucleic Acids Res., 2018, 46(W1), W350-W355.
[http://dx.doi.org/10.1093/nar/gky300] [PMID: 29718330]
[http://dx.doi.org/10.1093/nar/gky300] [PMID: 29718330]
[19]
van Zundert, G.C.P.; Rodrigues, J.P.G.L.M.; Trellet, M.; Schmitz, C.; Kastritis, P.L.; Karaca, E.; Melquiond, A.S.J.; van Dijk, M.; de Vries, S.J.; Bonvin, A.M.J.J. The HADDOCK2.2 web server: user-friendly integrative modeling of biomolecular complexes. J. Mol. Biol., 2016, 428(4), 720-725.
[http://dx.doi.org/10.1016/j.jmb.2015.09.014] [PMID: 26410586]
[http://dx.doi.org/10.1016/j.jmb.2015.09.014] [PMID: 26410586]
[20]
Khan, A.; Zia, T.; Suleman, M.; Khan, T.; Ali, S.S.; Abbasi, A.A.; Mohammad, A.; Wei, D.Q. Higher infectivity of the SARS-CoV-2 new variants is associated with K417N/T, E484K, and N501Y mutants: an insight from structural data. J. Cell. Physiol., 2021, 236(10), 7045-7057.
[http://dx.doi.org/10.1002/jcp.30367] [PMID: 33755190]
[http://dx.doi.org/10.1002/jcp.30367] [PMID: 33755190]
[21]
Ali, A.; Vijayan, R. Dynamics of the ACE2-SARS-CoV-2/SARS-CoV spike protein interface reveal unique mechanisms. Sci. Rep., 2020, 10(1), 14214.
[http://dx.doi.org/10.1038/s41598-020-71188-3] [PMID: 32848162]
[http://dx.doi.org/10.1038/s41598-020-71188-3] [PMID: 32848162]
[22]
Zahradnik, J.; Marciano, S.; Shemesh, M.; Zoler, E.; Chiaravalli, J.; Meyer, B.; Dym, O.; Elad, N.; Schreiber, G. SARS-CoV-2 RBD in vitro evolution follows contagious mutation spread, yet generates an able infection inhibitor. bioRxiv, 2021.
[http://dx.doi.org/10.1101/2021.01.06.425392]
[http://dx.doi.org/10.1101/2021.01.06.425392]
[23]
Mohammad, A. Characterisation of the effects of cosolutes on the stability of H-bonds in proteins by NMR spectroscopy. UCL; Universi-ty College London, 2012.
[24]
Greaney, A.J.; Loes, A.N.; Crawford, K.H.; Starr, T.N.; Malone, K.D.; Chu, H.Y.; Bloom, J.D. Comprehensive mapping of mutations to the SARS-CoV-2 receptor-binding domain that affect recognition by polyclonal human serum antibodies. bioRxiv, 2021, 2020; 2012.
[http://dx.doi.org/10.1101/2020.12.31.425021]
[http://dx.doi.org/10.1101/2020.12.31.425021]
[25]
Zhang, X.; Perez-Sanchez, H.; Lightstone, F.C. A comprehensive docking and MM/GBSA rescoring study of ligand recognition upon bind-ing antithrombin. Curr. Top. Med. Chem., 2017, 17(14), 1631-1639.
[http://dx.doi.org/10.2174/1568026616666161117112604] [PMID: 27852201]
[http://dx.doi.org/10.2174/1568026616666161117112604] [PMID: 27852201]
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