A comparative study of receptor interactions between SARS-CoV and SARS-CoV-2 from molecular modeling

Abstract

The pandemic of COVID-19 severe acute respiratory syndrome, which was fatal for millions of people worldwide, triggered the race to understand in detail the molecular mechanisms of this disease. In this work, the differences of interactions between the SARS-CoV/SARS-CoV-2 Receptor binding domain (RBD) and the human Angiotensin Converting Enzyme 2 (ACE2) receptor were studied using in silico tools. Our results show that SARS-CoV-2 RBD is more stable and forms more interactions with ACE2 than SARS-CoV. At its interface, three stable binding patterns are observed and named red-K31, green-K353 and blue-M82 according to the central ACE2 binding residue. In SARS-CoV instead, only the first two binding patches are persistently formed during the MD simulation. Our MM/GBSA calculations indicate the binding free energy difference of about 2.5 kcal/mol between SARS-CoV-2 and SARS-CoV which is compatible with the experiments. The binding free energy decomposition points out that SARS-CoV-2 RBD–ACE2 interactions of the red-K31 ($$-23.5~\pm ~0.2~kcal/mol$$ - 23.5 ± 0.2 k c a l / m o l ) and blue-M82 ($$-9.1~\pm ~0.1~kcal/mol$$ - 9.1 ± 0.1 k c a l / m o l ) patterns contribute more to the binding affinity than in SARS-CoV ($$-1.8~\pm ~0.02~kcal/mol$$ - 1.8 ± 0.02 k c a l / m o l for red-K31), while the contribution of the green-K353 pattern is very similar in the two strains ($$-17.8~\pm ~0.2~kcal/mol$$ - 17.8 ± 0.2 k c a l / m o l and $$-22.7~\pm ~0.1~kcal/mol$$ - 22.7 ± 0.1 k c a l / m o l for SARS-CoV-2 and SARS-CoV, respectively). Five groups of mutations draw our attention at the RBD–ACE2 binding interface, among them, the mutation –PPA469-471/GVEG482-485 has the most important and favorable impact on SARS-CoV-2 binding to the ACE2 receptor. These results, highlighting the molecular differences in the binding between the two viruses, contribute to the common knowledge about the new corona virus and to the development of appropriate antiviral treatments, addressing the necessity of ongoing pandemics.

Binding affinity between coronavirus spike protein and human ACE2 receptor

“…Taking SARS-CoV and SARS-CoV-2 as examples, results from in silico simulations of CoV S protein to hACE2 binding affinities appear to show greater inconsistency among themselves when compared to the in vitro SPR results [117] , [118] , [119] , [122] , [124] ( Fig. 5 ).…”

“…and model parameters which can lead to incomparable results. Chowdhury et al retrieved the SARS-CoV-2-hACE2 complex structure from PDB (ID: 6LZG) [117] where others used another one (ID: 6M0J) [118] , [119] , [122] , [124] . These studies used different binding free energy computation programs.…”

“…With the availability of the binding structure between the S protein of CoVs and the hACE2 receptor (such as SARS-CoV [64] and SARS-CoV-2 [105] ), it is possible to harness recent advances in computational power for the in silico prediction of the binding affinity between different CoV S proteins and hACE2. Computational methods include binding structure modeling, protein-protein docking simulations, and binding energy calculations [116] , [117] , [118] , [119] , [120] , [121] , [122] , [123] , [124] , [125] .…”

“…The lower the binding energy, the stronger the binding affinity between two proteins [142] . Several different programs have shown that the SARS-CoV-2 S protein and hACE2 complex has a lower free binding energy than the SARS-CoV S protein and hACE2 complex, therefore suggesting that the former has a stronger binding affinity for the ACE2 receptor [117] , [118] , [119] , [122] , [124] , [125] ( Fig. 5 ).…”

Investigating structural features of dimeric SARS-CoV-2 Mpro catalytic site with bound covalent ligands at physiological temperature

“…This cleft represents the binding site for inhibitors, most of them bind to the SARS-CoV-2 Mpro with a covalent bond. The X-ray structures of the SARS-CoV-2 Mpro in complex with different inhibitors were solved [4,5,6,7,8,9] and show that most inhibitors form a covalent bond with the SARS-CoV-2 Mpro catalytic residue C145. These covalent inhibitors have the electrophilic part, so called "warhead" that is binding to the nucleophilic residue of the target protein making the covalent bond.…”