Molecular dynamics analysis of a flexible loop at the binding interface of the SARS‐CoV ‐2 spike protein receptor‐binding domain
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Abstract
Since the identification of the SARS‐CoV‐2 virus as the causative agent of the current COVID‐19 pandemic, considerable effort has been spent characterizing the interaction between the Spike protein receptor‐binding domain (RBD) and the human angiotensin converting enzyme 2 (ACE2) receptor. This has provided a detailed picture of the end point structure of the RBD‐ACE2 binding event, but what remains to be elucidated is the conformation and dynamics of the RBD prior to its interaction with ACE2. In this work, we utilize molecular dynamics simulations to probe the flexibility and conformational ensemble of the unbound state of the receptor‐binding domain from SARS‐CoV‐2 and SARS‐CoV. We have found that the unbound RBD has a localized region of dynamic flexibility in Loop 3 and that mutations identified during the COVID‐19 pandemic in Loop 3 do not affect this flexibility. We use a loop‐modeling protocol to generate and simulate novel conformations of the CoV2‐RBD Loop 3 region that sample conformational space beyond the ACE2 bound crystal structure. This has allowed for the identification of interesting substates of the unbound RBD that are lower energy than the ACE2‐bound conformation, and that block key residues along the ACE2 binding interface. These novel unbound substates may represent new targets for therapeutic design.
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SciScore for 10.1101/2021.01.08.425965: (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 The simulations were performed with the GPU-enabled CUDA version of the pmemd module in the AMBER 2018 package30. AMBERsuggested: (AMBER, RRID:SCR_016151)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 …
SciScore for 10.1101/2021.01.08.425965: (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 The simulations were performed with the GPU-enabled CUDA version of the pmemd module in the AMBER 2018 package30. AMBERsuggested: (AMBER, RRID:SCR_016151)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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