Distinct Structural Flexibility within SARS-CoV-2 Spike Protein Reveals Potential Therapeutic Targets
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Abstract
The emergence and rapid worldwide spread of the novel coronavirus disease, COVID-19, has prompted concerted efforts to find successful treatments. The causative virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), uses its spike (S) protein to gain entry into host cells. Therefore, the S protein presents a viable target to develop a directed therapy. Here, we deployed an integrated artificial intelligence with molecular dynamics simulation approach to provide new details of the S protein structure. Based on a comprehensive structural analysis of S proteins from SARS-CoV-2 and previous human coronaviruses, we found that the protomer state of S proteins is structurally flexible. Without the presence of a stabilizing beta sheet from another protomer chain, two regions in the S2 domain and the hinge connecting the S1 and S2 subunits lose their secondary structures. Interestingly, the region in the S2 domain was previously identified as an immunodominant site in the SARS-CoV-1 S protein. We anticipate that the molecular details elucidated here will assist in effective therapeutic development for COVID-19.
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SciScore for 10.1101/2020.04.17.047548: (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
Experimental Models: Organisms/Strains Sentences Resources A. Molecular systems and MD simulations: To generate initial systems for the structural study of human coronavirus S proteins, we built protomer structures from chain A of the cryo-EM S protein structures of SARS-CoV-2 (PDB 6VSB [3]), SARS-CoV-1 (PDB 6CRZ [15]), MERS-CoV (PDB 6Q05 [16]), and HCoV-HKU1 (PDB 5I08 [14]). HCoV-HKU1 (PDB 5I08suggested: NoneSoftware and Algorithms Sentences Resources All MD simulations were performed with NAMD [22] in NPT ensemble at 1 atm and 310 K with a time step of 2 fs. NAMDsuggested: (NAMD, RRID:SCR_014894)For Input 1, as the proteins are … SciScore for 10.1101/2020.04.17.047548: (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
Experimental Models: Organisms/Strains Sentences Resources A. Molecular systems and MD simulations: To generate initial systems for the structural study of human coronavirus S proteins, we built protomer structures from chain A of the cryo-EM S protein structures of SARS-CoV-2 (PDB 6VSB [3]), SARS-CoV-1 (PDB 6CRZ [15]), MERS-CoV (PDB 6Q05 [16]), and HCoV-HKU1 (PDB 5I08 [14]). HCoV-HKU1 (PDB 5I08suggested: NoneSoftware and Algorithms Sentences Resources All MD simulations were performed with NAMD [22] in NPT ensemble at 1 atm and 310 K with a time step of 2 fs. NAMDsuggested: (NAMD, RRID:SCR_014894)For Input 1, as the proteins are different in length, we first performed a multiple sequence alignment of the protomer structures of SARS-CoV-2, SARS-CoV-1, MERS-CoV, and HCoV-HKU1 by Clustal Omega [29] Clustal Omegasuggested: (Clustal Omega, RRID:SCR_001591)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.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
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