On the interactions of the receptor-binding domain of SARS-CoV-1 and SARS-CoV-2 spike proteins with monoclonal antibodies and the receptor ACE2

Carolina Corrêa Giron; Aatto Laaksonen; Fernando L. Barroso da Silva

One of the central questions in the understanding of the COVID-19, its pathology including the high transmissibility, and the possible therapeutic interventions to control the epidemics spreading is to decipher and prevent the molecular interactions between the S protein and ACE2. 25 The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.04.05.026377 doi: bioRxiv preprint difference of 0.2nM could be due to several reasons including the experimental uncertainties that were not reported in Tian's work. 8 In contrast to these results, another recent study 20 advocated that SARS-CoV-2 has greater binding affinity for ACE2 than SARS-CoV-1. Even so, both the present theoretical and previously reported experimental data do agree that SARS-CoV-1 S RBD and SARS-CoV-2 S RBD have similar attraction to the ACE2. This high binding affinity implies that all human organs rich on ACE2 (oral and nasal mucosa, lung, stomach, small intestine, colon, skin, lymph nodes, thymus, bone marrow, spleen, liver, kidney, and brain) 76,77 can be easily infected. A clear opportunity for the virus is the lung alveolar epithelial cells and enterocytes of the small intestine, where ACE2 is abundant. 76 Note that the simulations were performed with a single RBD protein in the absence of the full structure of the S protein and the others two chains of the homotrimeric S glycoprotein. This brings with it the evidence that the other structural parts of the S1 subunit, the S2 subunit and the two other chains are not essential for the individual pair of RBD-ACE2 complexation. Also, this observation supports the argument that the dissociation of the S1 subunit complexed with ACE2 can happen without the interruption of the infection. This also allows the S2 subunit to transit from a metastable prefusion to its post-fusion state as a second step in the viral infection. 58, 78 At pH 4.6 which is closer to the low pH that occur outside the cell, 23 The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.04.05.026377 doi: bioRxiv preprint free-energy landscape must be interpreted with care as we already have pointed out above. By one side, it can be used a simple thermodynamic criterion that a negative free energy value (βwmin<0) would result in a molecular complex. Conversely, any free energy value smaller than the thermal energy (1 kBT) would indicate an unstable association. The observed difference ( βwmin) of 0.07 between the two RDB proteins is greater than the estimated statistical errors.