Understanding the molecular interaction of SARS-CoV-2 spike mutants with ACE2 (angiotensin converting enzyme 2)

Abstract

Covid-19 is a viral disease caused by the virus SARS-CoV-2 that spread worldwide and caused more than 4.3 million deaths. Moreover, SARS-CoV-2 still continues to evolve, and specifically the E484K, N501Y, and South Africa triple (K417N + E484K + N501Y) spike protein mutants remain as the ‘escape’ phenotypes. The aim of this study was to compare the interaction between the receptor binding domain (RBD) of the E484K, N501Y and South Africa triple spike variants and ACE2 with the interaction between wild-type spike RBD-ACE2 and to show whether the obtained binding affinities and conformations corraborate clinical findings. The structures of the RBDs of the E484K, N501Y and South Africa triple variants were generated with DS Studio v16 and energetically minimized using the CHARMM22 force field. Protein-protein dockings were performed in the HADDOCK server and the obtained wild-type and mutant spike-ACE2 complexes were submitted to 200-ns molecular dynamics simulations with subsequent free energy calculations using GROMACS. Based on docking binding affinities and free energy calculations the E484K, N501Y and triple mutant variants were found to interact stronger with the ACE2 than the wild-type spike. Interestingly, molecular dynamics and MM-PBSA results showed that E484K and spike triple mutant complexes were more stable than the N501Y one. Moreover, the E484K and South Africa triple mutants triggered greater conformational changes in the spike glycoprotein than N501Y. The E484K variant alone, or the combination of K417N + E484K + N501Y mutations induce significant conformational transitions in the spike glycoprotein, while increasing the spike-ACE2 binding affinity.

Communicated by Ramaswamy H. Sarma

Keywords:

• SARS-CoV-2
• escape mutants
• protein-protein docking
• molecular dynamics
• MM-PBSA

Acknowledgements

P. A. N. acknowledges financial support from CNPq and CAPES (Financial code 001), as well as the Centro Nacional de Supercomputação (CESUP), Universidade Federal do Rio Grande do Sul (UFRGS) for providing HPC resources.

Author contributions

E.S.I. conceptualized the study, performed protein-protein docking calculations, prepared Figures 1 and 2 and Tables 1 and 2, contributed to the writing and revision of the article; P.A.N. conducted the molecular dynamics simulations and MM/PBSA calculations, prepared Figures 3, 4, and 5 and Tables 3–4 , interpreted the results and contributed to the detailed revision of the manuscript; A.S.T. helped create and interpret Tables 1 and 2; C.S. contributed to the interpretation of protein-protein docking results; B.T. supervised E.S.I. and revised the manuscript. All the authors read and approved the final manuscript.

Disclosure statement

None of the authors declare conflict of interest in this work.

Additional information

Funding

Conselho Nacional de Desenvolvimento Científico e Tecnológico.