Interaction of the spike protein RBD from SARS-CoV-2 with ACE2: Similarity with SARS-CoV, hot-spot analysis and effect of the receptor polymorphism

Abstract

The spread of COVID-19 caused by the SARS-CoV-2 outbreak has been growing since its first identification in December 2019. The publishing of the first SARS-CoV-2 genome made a valuable source of data to study the details about its phylogeny, evolution, and interaction with the host. Protein-protein binding assays have confirmed that Angiotensin-converting enzyme 2 (ACE2) is more likely to be the cell receptor through which the virus invades the host cell. In the present work, we provide an insight into the interaction of the viral spike Receptor Binding Domain (RBD) from different coronavirus isolates with host ACE2 protein. By calculating the binding energy score between RBD and ACE2, we highlighted the putative jump in the affinity from a progenitor form of SARS-CoV-2 to the current virus responsible for COVID-19 outbreak. Our result was consistent with previously reported phylogenetic analysis and corroborates the opinion that the interface segment of the spike protein RBD might be acquired by SARS-CoV-2 via a complex evolutionary process rather than a progressive accumulation of mutations. We also highlighted the relevance of Q493 and P499 amino acid residues of SARS-CoV-2 RBD for binding to human ACE2 and maintaining the stability of the interface. Moreover, we show from the structural analysis that it is unlikely for the interface residues to be the result of genetic engineering. Finally, we studied the impact of eight different variants located at the interaction surface of ACE2, on the complex formation with SARS-CoV-2 RBD. We found that none of them is likely to disrupt the interaction with the viral RBD of SARS-CoV-2.

N-terminal domain (NTD) of SARS-CoV-2 spike-protein structurally resembles MERS-CoV NTD sialoside-binding pocket

“…The cryo-EM structures of SARS-CoV-2 (PDB ID: 6VXX) [8] and MERS-CoV (PDB ID: 6Q04) [10] spike glycoproteins were used as the starting point for all studies [8]. The full-length model of SARS-CoV-2 spike glycoprotein (YP_009724390.1) was strongly biased on the crystal structure of SARS-CoV-2, while the extended loops were rst modeled using MODELLER, version 9v24 using the model-loop procedure [15].…”

“…To identify if these three regions forms a part of domain or a functional module of NTD sequence, we modeled the full-length SARS-CoV-2 spike glycoprotein strongly biasing on the cryo-EM structure of SARS-CoV-2 spike protein (Fig 1c). The cryo-EM structures of SARS-CoV-2 spike protein display a well ordered β-strand rich NTD, RBD and the core helical domain [8]. Owing to their exibility, all β-β loops, except for β14-β15 displays almost no cryo-EM density even after B-factor sharpening.…”

“…After series of cleavages and conformational changes in the spike protein, SARS-CoV-2 fuses with target cellular membrane [6,7]. X-ray crystallography and cryo-electron microscopy studies along with in-vivo experiments con rm that SARS-CoV-2 entry in host cells is also achieved by the spike-ACE2 interaction [8]. However, recent study suggest limited ACE2 expression in the human respiratory system [9].…”

Novel anti-SARS-CoV-2 mechanisms of fusion broad range anti- infective protein ricin A chain mutant-pokeweed antiviral protein 1 (RTAM-PAP1) in silico

“…COVID-19 can cause severe symptoms such as damaging in ammatory response, fever or severe respiratory illness and lead to death. The causative agent of COVID-19 was found to be a novel coronavirus closely related to the severe acute respiratory syndrome coronavirus (SARS-CoV) based on the latest phylogenetic analysis [1][2][3] . There are nonetheless some major essential differences in their genetic make-up that led to their very different behaviors.…”

“…There are nonetheless some major essential differences in their genetic make-up that led to their very different behaviors. Indeed, SARS-CoV-2, as it is called now, appears to have a high transmissibility from person to person and antibodies that could inhibit SARS-CoV are not functional on SARS-CoV-2 2,[4][5] . Despite global efforts, we still lack an effective antiviral strategy, drug or vaccine to ght off this virus with the growing fear that SARS-COV-2 may become another endemic virus in our communities.…”