Biophysical characterization of the SARS-CoV-2 spike protein binding with the ACE2 receptor and implications for infectivity
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Abstract
SARS-CoV-2 is a novel highly virulent pathogen which gains entry to human cells by binding with the cell surface receptor – angiotensin converting enzyme (ACE2). We computationally contrasted the binding interactions between human ACE2 and coronavirus spike protein receptor binding domain (RBD) of the 2002 epidemic-causing SARS-CoV-1, SARS-CoV-2, and bat coronavirus RaTG13 using the Rosetta energy function. We find that the RBD of the spike protein of SARS-CoV-2 is highly optimized to achieve very strong binding with human ACE2 (hACE2) which is consistent with its enhanced infectivity. SARS-CoV-2 forms the most stable complex with hACE2 compared to SARS-CoV-1 (23% less stable) or RaTG13 (11% less stable) while occupying the greatest number of residues in the ATR1 binding site. Notably, the SARS-CoV-2 RBD out-competes the angiotensin 2 receptor type I (ATR1) which is the native binding partner of ACE2 by 35% in terms of the calculated binding affinity. Strong binding is mediated through strong electrostatic attachments with every fourth residue on the N-terminus alpha-helix (starting from Ser19 to Asn53) as the turn of the helix makes these residues solvent accessible. By contrasting the spike protein SARS-CoV-2 Rosetta binding energy with ACE2 of different livestock and pet species we find strongest binding with bat ACE2 followed by human, feline, equine, canine and finally chicken. This is consistent with the hypothesis that bats are the viral origin and reservoir species. These results offer a computational explanation for the increased infectivity of SARS-CoV-2 and allude to therapeutic modalities by identifying and rank-ordering the ACE2 residues involved in binding with the virus.
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SciScore for 10.1101/2020.03.30.015891: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Software and Algorithms Sentences Resources Subsequently, PyRosetta21 scripts were written to rank and identify the most stable complexes from each cluster which were then energy-minimized and re-ranked. PyRosetta21suggested: NoneAn alanine scan was again performed using PyRosetta scripts, where the computational models of the alanine variants were first generated, energy minimized, and hACE2 binding scores computed. PyRosettasuggested: (PyRosetta, RRID:SCR_018541)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results …SciScore for 10.1101/2020.03.30.015891: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Software and Algorithms Sentences Resources Subsequently, PyRosetta21 scripts were written to rank and identify the most stable complexes from each cluster which were then energy-minimized and re-ranked. PyRosetta21suggested: NoneAn alanine scan was again performed using PyRosetta scripts, where the computational models of the alanine variants were first generated, energy minimized, and hACE2 binding scores computed. PyRosettasuggested: (PyRosetta, RRID:SCR_018541)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- No funding statement was detected.
- No protocol registration statement was detected.
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