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

Strain Wars: Competitive interactions between SARS-CoV-2 strains are explained by Gibbs energy of antigen-receptor binding

“…The ability of coronaviruses to infect humans is invariably associated with their binding strengths to human receptor proteins (Junjie et al 2020). Mutation induces significant conformational transitions in the spike glycoprotein ( Istifli et al, 2021 ). Natural selection promotes mutations that increase the spike ACE2 binding affinity ( Istifli et al, 2021 ).…”

“…Mutation induces significant conformational transitions in the spike glycoprotein ( Istifli et al, 2021 ). Natural selection promotes mutations that increase the spike ACE2 binding affinity ( Istifli et al, 2021 ). Gibbs energy of binding can be calculated from dissociation constants, through the equation Where R is the universal gas constant and T temperature ( Popovic & Minceva, 2021 ; Du et al, 2016 ).…”

Decreased Interfacial Dynamics Caused by the N501Y Mutation in the SARS-CoV-2 S1 Spike:ACE2 Complex

“…These highlights the vital role of N501Y in increasing the binding affinity to ACE2, thereby decelerating rate of dissociation from the ACE2 receptor in comparison to the WT. (Tian, 2021a;Istifli et al, 2021;Villoutreix et al, 2021) Computational studies by Socher et al, showed increased contact at 501 when tyrosine is present. (Socher et al, 2021) Additional studies have shown high number of contacts formed by residues F486, Y489, T500 and Y505 with ACE2 receptor.…”

COVID-19 Genetic Variants and Their Potential Impact in Vaccine Development

“…Among them, K417N also appeared in the Beta variant. Structure predictions revealed that these three mutations could result in significant changes to the receptor-binding domain of the spike protein, resulting in stronger ACE2 binding [ 21 ]. Patients carrying variants in SARS-CoV-2 residue 484 (E484K, E484Q or E484P) showed a reduced ability to neutralize the infection by polyclonal antibodies.…”