Structural dynamics of the β-coronavirus M pro protease ligand binding sites
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Abstract
β-coronaviruses alone have been responsible for three major global outbreaks in the 21 st century. The current crisis has led to an urgent requirement to develop therapeutics. Even though a number of vaccines are available, alternative strategies targeting essential viral components are required as a back-up against the emergence of lethal viral variants. One such target is the main protease (M pro ) that plays an indispensible role in viral replication. The availability of over 270 M pro X-ray structures in complex with inhibitors provides unique insights into ligand-protein interactions. Herein, we provide a comprehensive comparison of all non-redundant ligand-binding sites available for SARS-CoV2, SARS-CoV and MERS-CoV M pro . Extensive adaptive sampling has been used to explore conformational dynamics employing convolutional variational auto encoder-based deep learning, and investigates structural conservation of the ligand binding sites using Markov state models across β-coronavirus homologs. Our results indicate that not all ligand-binding sites are dynamically conserved despite high sequence and structural conservation across β-coronavirus homologs. This highlights the complexity in targeting all three M pro enzymes with a single pan inhibitor.
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SciScore for 10.1101/2021.03.31.437918: (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 MSM was built using the PyEMMA v2.5.7 program. PyEMMAsuggested: NoneThe conformational clusters were grouped together based on kinetic similarity using the PCCA+ algorithm.70 The PCCA+ algorithm uses the eigenvectors of the MSMs to group together clusters, which are kinetically close, resulting in a set of macrostates. MSMssuggested: (MSMS, RRID:SCR_003532)Results from OddPub: Thank you for sharing your data.
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 …SciScore for 10.1101/2021.03.31.437918: (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 MSM was built using the PyEMMA v2.5.7 program. PyEMMAsuggested: NoneThe conformational clusters were grouped together based on kinetic similarity using the PCCA+ algorithm.70 The PCCA+ algorithm uses the eigenvectors of the MSMs to group together clusters, which are kinetically close, resulting in a set of macrostates. MSMssuggested: (MSMS, RRID:SCR_003532)Results from OddPub: Thank you for sharing your data.
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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