Large Interfacial Relocation in RBD-ACE2 Complex May Explain Fast-spreading Property of Omicron

Overview

Journal J Mol Struct

Publisher Elsevier

Specialty Chemistry

Date 2022 Aug 8

PMID 35937157

Authors

Maryam Shirzadeh

Hassan Monhemi

Mohammad Eftekhari

Affiliations

Soon will be listed here.

Abstract

The Omicron variant of SARS-CoV-2 emerged in South African in late 2021. This variant has a large number of mutations, and regarded as fastest-spreading Covid variant. The spike RBD region of SARS-CoV-2 and its interaction with human ACE2 play fundamental role in viral infection and transmission. To explore the reason of fast-spreading properties of Omicron variant, we have modeled the interactions of Omicron RBD and human ACE2 using docking and molecular dynamics simulations. Results show that RBD-ACE2 binding site may drastically relocate with an enlarged interface. The predicted interface has large negative binding energies and shows stable conformation in molecular dynamics simulations. It was found that the interfacial area in Omicron RBD-ACE2 complex is increased up to 40% in comparison to wild-type Sars-Cov-2. Moreover, the number of hydrogen bonds significantly increased up to 80%. The key interacting residues become also very different in Omicron variant. The new binding interface can significantly accommodate R403, as a key RBD residue, near ACE2 surface which leads to two new strong salt bridges. The exploration of the new binding interface can help to understand the reasons of high transmission rate of Omicron.

References

Zech F, Schniertshauer D, Jung C, Herrmann A, Cordsmeier A, Xie Q . Spike residue 403 affects binding of coronavirus spikes to human ACE2. Nat Commun. 2021; 12(1):6855. PMC: 8617078. DOI: 10.1038/s41467-021-27180-0. View

Harapan H, Itoh N, Yufika A, Winardi W, Keam S, Te H . Coronavirus disease 2019 (COVID-19): A literature review. J Infect Public Health. 2020; 13(5):667-673. PMC: 7142680. DOI: 10.1016/j.jiph.2020.03.019. View

Singhal T . A Review of Coronavirus Disease-2019 (COVID-19). Indian J Pediatr. 2020; 87(4):281-286. PMC: 7090728. DOI: 10.1007/s12098-020-03263-6. View

Laurini E, Marson D, Aulic S, Fermeglia A, Pricl S . Computational Mutagenesis at the SARS-CoV-2 Spike Protein/Angiotensin-Converting Enzyme 2 Binding Interface: Comparison with Experimental Evidence. ACS Nano. 2021; 15(4):6929-6948. PMC: 8009103. DOI: 10.1021/acsnano.0c10833. View

Williams A, Zhan C . Fast Prediction of Binding Affinities of the SARS-CoV-2 Spike Protein Mutant N501Y (UK Variant) with ACE2 and Miniprotein Drug Candidates. J Phys Chem B. 2021; 125(17):4330-4336. PMC: 8084269. DOI: 10.1021/acs.jpcb.1c00869. View

Pan A, Jacobson D, Yatsenko K, Sritharan D, Weinreich T, Shaw D . Atomic-level characterization of protein-protein association. Proc Natl Acad Sci U S A. 2019; 116(10):4244-4249. PMC: 6410769. DOI: 10.1073/pnas.1815431116. View

Vangone A, Spinelli R, Scarano V, Cavallo L, Oliva R . COCOMAPS: a web application to analyze and visualize contacts at the interface of biomolecular complexes. Bioinformatics. 2011; 27(20):2915-6. DOI: 10.1093/bioinformatics/btr484. View

Moreira I, Fernandes P, Ramos M . Hot spots--a review of the protein-protein interface determinant amino-acid residues. Proteins. 2007; 68(4):803-12. DOI: 10.1002/prot.21396. View

Laurini E, Marson D, Aulic S, Fermeglia M, Pricl S . Computational Alanine Scanning and Structural Analysis of the SARS-CoV-2 Spike Protein/Angiotensin-Converting Enzyme 2 Complex. ACS Nano. 2020; 14(9):11821-11830. PMC: 7448377. DOI: 10.1021/acsnano.0c04674. View

10.

Lan J, Ge J, Yu J, Shan S, Zhou H, Fan S . Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. Nature. 2020; 581(7807):215-220. DOI: 10.1038/s41586-020-2180-5. View

11.

Dominguez C, Boelens R, Bonvin A . HADDOCK: a protein-protein docking approach based on biochemical or biophysical information. J Am Chem Soc. 2003; 125(7):1731-7. DOI: 10.1021/ja026939x. View

12.

Lim H, Baek A, Kim J, Kim M, Liu J, Nam K . Hot spot profiles of SARS-CoV-2 and human ACE2 receptor protein protein interaction obtained by density functional tight binding fragment molecular orbital method. Sci Rep. 2020; 10(1):16862. PMC: 7544872. DOI: 10.1038/s41598-020-73820-8. View

13.

Harvey W, Carabelli A, Jackson B, Gupta R, Thomson E, Harrison E . SARS-CoV-2 variants, spike mutations and immune escape. Nat Rev Microbiol. 2021; 19(7):409-424. PMC: 8167834. DOI: 10.1038/s41579-021-00573-0. View

14.

Keskin O, Ma B, Nussinov R . Hot regions in protein--protein interactions: the organization and contribution of structurally conserved hot spot residues. J Mol Biol. 2005; 345(5):1281-94. DOI: 10.1016/j.jmb.2004.10.077. View

15.

Shang J, Ye G, Shi K, Wan Y, Luo C, Aihara H . Structural basis of receptor recognition by SARS-CoV-2. Nature. 2020; 581(7807):221-224. PMC: 7328981. DOI: 10.1038/s41586-020-2179-y. View

16.

Martinez L . Automatic identification of mobile and rigid substructures in molecular dynamics simulations and fractional structural fluctuation analysis. PLoS One. 2015; 10(3):e0119264. PMC: 4376797. DOI: 10.1371/journal.pone.0119264. View

17.

Moreira I, Koukos P, Melo R, Almeida J, Preto A, Schaarschmidt J . SpotOn: High Accuracy Identification of Protein-Protein Interface Hot-Spots. Sci Rep. 2017; 7(1):8007. PMC: 5556074. DOI: 10.1038/s41598-017-08321-2. View

18.

Feng Z, Alqarni M, Yang P, Tong Q, Chowdhury A, Wang L . Modeling, molecular dynamics simulation, and mutation validation for structure of cannabinoid receptor 2 based on known crystal structures of GPCRs. J Chem Inf Model. 2014; 54(9):2483-99. PMC: 4170816. DOI: 10.1021/ci5002718. View

19.

van Zundert G, Rodrigues J, Trellet M, Schmitz C, Kastritis P, Karaca E . The HADDOCK2.2 Web Server: User-Friendly Integrative Modeling of Biomolecular Complexes. J Mol Biol. 2015; 428(4):720-725. DOI: 10.1016/j.jmb.2015.09.014. View

20.

Hu B, Guo H, Zhou P, Shi Z . Characteristics of SARS-CoV-2 and COVID-19. Nat Rev Microbiol. 2020; 19(3):141-154. PMC: 7537588. DOI: 10.1038/s41579-020-00459-7. View