Role of changes in SARS-CoV-2 spike protein in the interaction with the human ACE2 receptor: An in silico analysis

Abstract

Many human viral diseases are a consequence of a zoonotic event. Some of the diseases caused by these zoonotic events have affected millions of people around the world, some of which have resulted in high rates of morbidity/mortality in humans. Changes in the viral proteins that function as ligands of the host receptor may promote the spillover between species. The most recent of these zoonotic events that have caused an ongoing epidemic of high magnitude is the Covid-19 epidemics caused by SARS-CoV-2. The aim of this study was to determine the mutation(s) in the sequence of the spike protein of the SARS-CoV-2 that might be favoring human to human transmission. An in silico approach was performed, and changes were detected in the S1 subunit of the receptor-binding domain of spike. The observed changes have significant effect on SARS-CoV-2 spike/ACE2 interaction and produce a reduction in the binding energy, compared to the one of the Bat-CoV to this receptor. The data presented in this study suggest a higher affinity of the SARS-Cov-2 spike protein to the human ACE2 receptor, compared to the one of Bat-CoV spike and ACE2. This could be the cause of the rapid viral spread of SARS-CoV-2 in humans.

Keywords: ACE2; Coronavirus; SARS-CoV-2; Spike; outbreak.

Table 1. Residues involved in the Interaction between viral spike and ACE2 (SARS)

Table 2. Number of protein-protein contacts (PPC) between CoV spikes and ACE2

Table 3. Binding affinity (ΔG) and dissociation constant (Kd) predicted values for the interaction between viral spike and ACE2 receptor

Figure 1. Phylogenetic analysis of SARS-CoV-2 and other coronavirus spike proteins. Phylogenetic tree constructed with Poisson correction and 100 bootstrap replicas. The sequences are named with their accession number. Percent homology with SARS-CoV-2 spike protein is shown for some proteins.

Figure 2. Receptor Binding Domain of the spike protein sequence alignment of SARS-CoV-2 and other related Coronaviruses. Sequence aligment for the interacting domain of SARS-CoV-2 (MN938384), Bat-CoV (MN996532 and MG772933) and SARS-CoV (NC004718). The key amino acids described for the interaction with ACE2 are shown in red, and in blue others amino acid related with the interaction in SARS-CoV2. (Lines (-) = same amino acid, dots (.) =deletion)

Figure 3. Coronavirus spike proteins. The spike proteins in complex with the RBD of ACE2 (dark pink) are shown A) Bat-CoV, B) SARS-CoV, and C) SARS-CoV-2. A comparison between the three spike proteins are shown in D and a 45 degree turn is also shown in E. The location of the main residues mutated in SARS-CoV (position 479 and 487) and SARS-CoV-2 are shown in F (green and blue).