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Modeling SARS-CoV-2 spike/ACE2 protein-protein interactions for predicting the binding affinity of new spike variants for ACE2, and novel ACE2 structurally related human protein targets, for COVID-19 handling in the 3PM context.
EPMA J. 2022 Mar; 13(1):149-175.EJ

Abstract

Aims

The rapid spread of new SARS-CoV-2 variants has highlighted the crucial role played in the infection by mutations occurring at the SARS-CoV-2 spike receptor binding domain (RBD) in the interactions with the human ACE2 receptor. In this context, it urgently needs to develop new rapid tools for quickly predicting the affinity of ACE2 for the SARS-CoV-2 spike RBD protein variants to be used with the ongoing SARS-CoV-2 genomic sequencing activities in the clinics, aiming to gain clues about the transmissibility and virulence of new variants, to prevent new outbreaks and to quickly estimate the severity of the disease in the context of the 3PM.

Methods

In our study, we used a computational pipeline for calculating the interaction energies at the SARS-CoV-2 spike RBD/ACE2 protein-protein interface for a selected group of characterized infectious variants of concern/interest (VoC/VoI). By using our pipeline, we built 3D comparative models of the SARS-CoV-2 spike RBD/ACE2 protein complexes for the VoC B.1.1.7-United Kingdom (carrying the mutations of concern/interest N501Y, S494P, E484K at the RBD), P.1-Japan/Brazil (RBD mutations: K417T, E484K, N501Y), B.1.351-South Africa (RBD mutations: K417N, E484K, N501Y), B.1.427/B.1.429-California (RBD mutations: L452R), the B.1.141 (RBD mutations: N439K), and the recent B.1.617.1-India (RBD mutations: L452R; E484Q) and the B.1.620 (RBD mutations: S477N; E484K). Then, we used the obtained 3D comparative models of the SARS-CoV-2 spike RBD/ACE2 protein complexes for predicting the interaction energies at the protein-protein interface.

Results

Along SARS-CoV-2 mutation database screening and mutation localization analysis, it was ascertained that the most dangerous mutations at VoC/VoI spike proteins are located mainly at three regions of the SARS-CoV-2 spike "boat-shaped" receptor binding motif, on the RBD domain. Notably, the P.1 Japan/Brazil variant present three mutations, K417T, E484K, N501Y, located along the entire receptor binding motif, which apparently determines the highest interaction energy at the SARS-CoV-2 spike RBD/ACE2 protein-protein interface, among those calculated. Conversely, it was also observed that the replacement of a single acidic/hydrophilic residue with a basic residue (E484K or N439K) at the "stern" or "bow" regions, of the boat-shaped receptor binding motif on the RBD, appears to determine an interaction energy with ACE2 receptor higher than that observed with single mutations occurring at the "hull" region or with other multiple mutants. In addition, our pipeline allowed searching for ACE2 structurally related proteins, i.e., THOP1 and NLN, which deserve to be investigated for their possible involvement in interactions with the SARS-CoV-2 spike protein, in those tissues showing a low expression of ACE2, or as a novel receptor for future spike variants. A freely available web-tool for the in silico calculation of the interaction energy at the SARS-CoV-2 spike RBD/ACE2 protein-protein interface, starting from the sequences of the investigated spike and/or ACE2 variants, was made available for the scientific community at: https://www.mitoairm.it/covid19affinities.

Conclusion

In the context of the PPPM/3PM, the employment of the described pipeline through the provided webservice, together with the ongoing SARS-CoV-2 genomic sequencing, would help to predict the transmissibility of new variants sequenced from future patients, depending on SARS-CoV-2 genomic sequencing activities and on the specific amino acid replacement and/or on its location on the SARS-CoV-2 spike RBD, to put in play all the possible counteractions for preventing the most deleterious scenarios of new outbreaks, taking into consideration that a greater transmissibility has not to be necessarily related to a more severe manifestation of the disease.

Supplementary Information

The online version contains supplementary material available at 10.1007/s13167-021-00267-w.

Authors+Show Affiliations

Department of Biosciences, Biotechnologies, Biopharmaceutics, University of Bari, Via E. Orabona, 4, 70125 Bari, Italy.Department of Biosciences, Biotechnologies, Biopharmaceutics, University of Bari, Via E. Orabona, 4, 70125 Bari, Italy.Department of Biosciences, Biotechnologies, Biopharmaceutics, University of Bari, Via E. Orabona, 4, 70125 Bari, Italy.Department of Biosciences, Biotechnologies, Biopharmaceutics, University of Bari, Via E. Orabona, 4, 70125 Bari, Italy.Department of Biosciences, Biotechnologies, Biopharmaceutics, University of Bari, Via E. Orabona, 4, 70125 Bari, Italy.Department of Sciences, University of Basilicata, Viale dell'Ateneo Lucano, 10-85100 Potenza, Italy.Department of Biosciences, Biotechnologies, Biopharmaceutics, University of Bari, Via E. Orabona, 4, 70125 Bari, Italy.Department of Biosciences, Biotechnologies, Biopharmaceutics, University of Bari, Via E. Orabona, 4, 70125 Bari, Italy. BROWSer S.r.l. at Department of Biosciences, Biotechnologies, Biopharmaceutics, University "Aldo Moro" of Bari, Via E. Orabona, 4, 70126 Bari, Italy.Department of Biosciences, Biotechnologies, Biopharmaceutics, University of Bari, Via E. Orabona, 4, 70125 Bari, Italy. BROWSer S.r.l. at Department of Biosciences, Biotechnologies, Biopharmaceutics, University "Aldo Moro" of Bari, Via E. Orabona, 4, 70126 Bari, Italy.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

35013687

Citation

Tragni, Vincenzo, et al. "Modeling SARS-CoV-2 spike/ACE2 Protein-protein Interactions for Predicting the Binding Affinity of New Spike Variants for ACE2, and Novel ACE2 Structurally Related Human Protein Targets, for COVID-19 Handling in the 3PM Context." The EPMA Journal, vol. 13, no. 1, 2022, pp. 149-175.
Tragni V, Preziusi F, Laera L, et al. Modeling SARS-CoV-2 spike/ACE2 protein-protein interactions for predicting the binding affinity of new spike variants for ACE2, and novel ACE2 structurally related human protein targets, for COVID-19 handling in the 3PM context. EPMA J. 2022;13(1):149-175.
Tragni, V., Preziusi, F., Laera, L., Onofrio, A., Mercurio, I., Todisco, S., Volpicella, M., De Grassi, A., & Pierri, C. L. (2022). Modeling SARS-CoV-2 spike/ACE2 protein-protein interactions for predicting the binding affinity of new spike variants for ACE2, and novel ACE2 structurally related human protein targets, for COVID-19 handling in the 3PM context. The EPMA Journal, 13(1), 149-175. https://doi.org/10.1007/s13167-021-00267-w
Tragni V, et al. Modeling SARS-CoV-2 spike/ACE2 Protein-protein Interactions for Predicting the Binding Affinity of New Spike Variants for ACE2, and Novel ACE2 Structurally Related Human Protein Targets, for COVID-19 Handling in the 3PM Context. EPMA J. 2022;13(1):149-175. PubMed PMID: 35013687.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Modeling SARS-CoV-2 spike/ACE2 protein-protein interactions for predicting the binding affinity of new spike variants for ACE2, and novel ACE2 structurally related human protein targets, for COVID-19 handling in the 3PM context. AU - Tragni,Vincenzo, AU - Preziusi,Francesca, AU - Laera,Luna, AU - Onofrio,Angelo, AU - Mercurio,Ivan, AU - Todisco,Simona, AU - Volpicella,Mariateresa, AU - De Grassi,Anna, AU - Pierri,Ciro Leonardo, Y1 - 2022/01/06/ PY - 2021/09/14/received PY - 2021/12/04/accepted PY - 2022/1/12/pubmed PY - 2022/1/12/medline PY - 2022/1/11/entrez KW - ACE2 structurally related proteins KW - Angiotensin-converting enzyme II (ACE2) KW - COVID-19 KW - Improved individual outcomes KW - In silico analysis KW - Interaction energies KW - Modelling KW - Mutant localization KW - Neurolysin (NLN) KW - Predictive software KW - Predictive, Preventive and personalized medicine (PPPM/3PM) KW - Protein–protein interaction KW - Receptor binding domain (RBD) KW - Receptor binding motif (RBM) KW - SARS-CoV-2 cell entry-factors KW - SARS-CoV-2 spike variants KW - Targeted therapy KW - Thimet oligopeptidase (THOP1) KW - Transmissibility and virulence prediction SP - 149 EP - 175 JF - The EPMA journal JO - EPMA J VL - 13 IS - 1 N2 - Aims: The rapid spread of new SARS-CoV-2 variants has highlighted the crucial role played in the infection by mutations occurring at the SARS-CoV-2 spike receptor binding domain (RBD) in the interactions with the human ACE2 receptor. In this context, it urgently needs to develop new rapid tools for quickly predicting the affinity of ACE2 for the SARS-CoV-2 spike RBD protein variants to be used with the ongoing SARS-CoV-2 genomic sequencing activities in the clinics, aiming to gain clues about the transmissibility and virulence of new variants, to prevent new outbreaks and to quickly estimate the severity of the disease in the context of the 3PM. Methods: In our study, we used a computational pipeline for calculating the interaction energies at the SARS-CoV-2 spike RBD/ACE2 protein-protein interface for a selected group of characterized infectious variants of concern/interest (VoC/VoI). By using our pipeline, we built 3D comparative models of the SARS-CoV-2 spike RBD/ACE2 protein complexes for the VoC B.1.1.7-United Kingdom (carrying the mutations of concern/interest N501Y, S494P, E484K at the RBD), P.1-Japan/Brazil (RBD mutations: K417T, E484K, N501Y), B.1.351-South Africa (RBD mutations: K417N, E484K, N501Y), B.1.427/B.1.429-California (RBD mutations: L452R), the B.1.141 (RBD mutations: N439K), and the recent B.1.617.1-India (RBD mutations: L452R; E484Q) and the B.1.620 (RBD mutations: S477N; E484K). Then, we used the obtained 3D comparative models of the SARS-CoV-2 spike RBD/ACE2 protein complexes for predicting the interaction energies at the protein-protein interface. Results: Along SARS-CoV-2 mutation database screening and mutation localization analysis, it was ascertained that the most dangerous mutations at VoC/VoI spike proteins are located mainly at three regions of the SARS-CoV-2 spike "boat-shaped" receptor binding motif, on the RBD domain. Notably, the P.1 Japan/Brazil variant present three mutations, K417T, E484K, N501Y, located along the entire receptor binding motif, which apparently determines the highest interaction energy at the SARS-CoV-2 spike RBD/ACE2 protein-protein interface, among those calculated. Conversely, it was also observed that the replacement of a single acidic/hydrophilic residue with a basic residue (E484K or N439K) at the "stern" or "bow" regions, of the boat-shaped receptor binding motif on the RBD, appears to determine an interaction energy with ACE2 receptor higher than that observed with single mutations occurring at the "hull" region or with other multiple mutants. In addition, our pipeline allowed searching for ACE2 structurally related proteins, i.e., THOP1 and NLN, which deserve to be investigated for their possible involvement in interactions with the SARS-CoV-2 spike protein, in those tissues showing a low expression of ACE2, or as a novel receptor for future spike variants. A freely available web-tool for the in silico calculation of the interaction energy at the SARS-CoV-2 spike RBD/ACE2 protein-protein interface, starting from the sequences of the investigated spike and/or ACE2 variants, was made available for the scientific community at: https://www.mitoairm.it/covid19affinities. Conclusion: In the context of the PPPM/3PM, the employment of the described pipeline through the provided webservice, together with the ongoing SARS-CoV-2 genomic sequencing, would help to predict the transmissibility of new variants sequenced from future patients, depending on SARS-CoV-2 genomic sequencing activities and on the specific amino acid replacement and/or on its location on the SARS-CoV-2 spike RBD, to put in play all the possible counteractions for preventing the most deleterious scenarios of new outbreaks, taking into consideration that a greater transmissibility has not to be necessarily related to a more severe manifestation of the disease. Supplementary Information: The online version contains supplementary material available at 10.1007/s13167-021-00267-w. SN - 1878-5077 UR - https://www.unboundmedicine.com/medline/citation/35013687/Modeling_SARS_CoV_2_spike/ACE2_protein_protein_interactions_for_predicting_the_binding_affinity_of_new_spike_variants_for_ACE2_and_novel_ACE2_structurally_related_human_protein_targets_for_COVID_19_handling_in_the_3PM_context_ L2 - https://dx.doi.org/10.1007/s13167-021-00267-w DB - PRIME DP - Unbound Medicine ER -