In Silico Investigation of the New UK (B.1.1.7) and South African (501Y.V2) SARS-CoV-2 Variants with a Focus at the ACE2–Spike RBD Interface
This article has been Reviewed by the following groups
Listed in
- Evaluated articles (ScreenIT)
Abstract
SARS-CoV-2 exploits angiotensin-converting enzyme 2 (ACE2) as a receptor to invade cells. It has been reported that the UK and South African strains may have higher transmission capabilities, eventually in part due to amino acid substitutions on the SARS-CoV-2 Spike protein. The pathogenicity seems modified but is still under investigation. Here we used the experimental structure of the Spike RBD domain co-crystallized with part of the ACE2 receptor, several in silico methods and numerous experimental data reported recently to analyze the possible impacts of three amino acid replacements (Spike K417N, E484K, N501Y) with regard to ACE2 binding. We found that the N501Y replacement in this region of the interface (present in both the UK and South African strains) should be favorable for the interaction with ACE2, while the K417N and E484K substitutions (South African strain) would seem neutral or even unfavorable. It is unclear if the N501Y substitution in the South African strain could counterbalance the K417N and E484K Spike replacements with regard to ACE2 binding. Our finding suggests that the UK strain should have higher affinity toward ACE2 and therefore likely increased transmissibility and possibly pathogenicity. If indeed the South African strain has a high transmission level, this could be due to the N501Y replacement and/or to substitutions in regions located outside the direct Spike–ACE2 interface but not so much to the K417N and E484K replacements. Yet, it should be noted that amino acid changes at Spike position 484 can lead to viral escape from neutralizing antibodies. Further, these amino acid substitutions do not seem to induce major structural changes in this region of the Spike protein. This structure–function study allows us to rationalize some observations made for the UK strain but raises questions for the South African strain.
Article activity feed
-
-
SciScore for 10.1101/2021.01.24.427939: (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 Amino acid substitutions in the Spike protein were done using PyMol while a short energy minimization of each modified 3D complex was carried out with UCSF Chimera. PyMolsuggested: (PyMOL, RRID:SCR_000305)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: We detected the following sentences addressing limitations in the study:
Different types of computational tools (https://www.vls3d.com/), all with strengths and weaknesses, can be used to …
SciScore for 10.1101/2021.01.24.427939: (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 Amino acid substitutions in the Spike protein were done using PyMol while a short energy minimization of each modified 3D complex was carried out with UCSF Chimera. PyMolsuggested: (PyMOL, RRID:SCR_000305)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: We detected the following sentences addressing limitations in the study:
Different types of computational tools (https://www.vls3d.com/), all with strengths and weaknesses, can be used to investigate the possible impacts of amino acid replacements on the structure and function of a protein when a 3D structure is available or can be predicted [25–32]. It is recommended to use different tools that apply different types of algorithms so as to gain some “consensus” insights about the amino-acid replacement [25]. Further, when experimental data are available, it is obviously of interest to select methods that can at least reproduce such data. The present investigation benefits from the recently published Spike mutagenesis study and the impacts on ACE2 binding [19]. Among the experimental data reported in that study, we were particularly interested in the measured affinity of the Spike N501F protein mutant with ACE2 as it involves residue 501 and as the affinity was assessed in a purified binding assay (most other affinity evaluation were performed using high-throughput affinity measurements that could be less accurate than measurements carried out in purified systems). Experimentally, it was found that the Spike N501F protein has increased affinity for ACE2. Interestingly, most in silico tools that we tested to compute stability changes at protein interfaces (ΔΔG) could not reproduce this measurement. We noted that the SPServer and pyDockEneRes tools were able to output data consistent with this high-quality N501F experimental result. Our selection doe...
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 scite Reference Check: We found no unreliable references.
About SciScore
SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.
-
SciScore for 10.1101/2021.01.24.427939: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
Software and Algorithms Sentences Resources The interactive structural analysis was performed with PyMol (Schrödinger product) and UCSF ChimeraX (32881101). PyMolsuggested: (PyMOL, RRID:SCR_000305)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: We …
SciScore for 10.1101/2021.01.24.427939: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
Software and Algorithms Sentences Resources The interactive structural analysis was performed with PyMol (Schrödinger product) and UCSF ChimeraX (32881101). PyMolsuggested: (PyMOL, RRID:SCR_000305)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: We detected the following sentences addressing limitations in the study:
Different types of computational tools (https://www.vls3d.com/), all with strengths and weaknesses, can be used to investigate the possible impacts of amino acid replacements on the structure and function of a protein when a 3D structure is available or can be predicted [25–32]. It is recommended to use different tools that apply different types of algorithms so as to gain some “consensus” insights about the amino-acid replacement [25]. Further, when experimental data are available, it is obviously of interest to select methods that can at least reproduce such data. The present investigation benefits from the recently published Spike mutagenesis study and the impacts on ACE2 binding [19]. Among the experimental data reported in that study, we were particularly interested in the measured affinity of the Spike N501F protein mutant with ACE2 as it involves residue 501 and as the affinity was assessed in a purified binding assay (most other affinity evaluation were performed using highthroughput affinity measurements that could be less accurate than measurements carried out in purified systems). Experimentally, it was found that the Spike N501F protein has increased affinity for ACE2. Interestingly, most in silico tools that we tested to compute stability changes at protein interfaces (ΔΔG) could not reproduce this measurement. We noted that the SPServer and pyDockEneRes tools were able to output data consistent with this high-quality N501F experimental result. Our selection does...
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.
About SciScore
SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.
-
