A novel consensus‐based computational pipeline for screening of antibody therapeutics for efficacy against SARS‐CoV‐2 variants of concern including Omicron variant
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Abstract
Multiple severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) variants continue to evolve carrying flexible amino acid substitutions in the spike protein's receptor binding domain (RBD). These substitutions modify the binding of the SARS‐CoV‐2 to human angiotensin‐converting enzyme 2 (hACE2) receptor and have been implicated in altered host fitness, transmissibility, and efficacy against antibody therapeutics and vaccines. Reliably predicting the binding strength of SARS‐CoV‐2 variants RBD to hACE2 receptor and neutralizing antibodies (NAbs) can help assessing their fitness, and rapid deployment of effective antibody therapeutics, respectively. Here, we introduced a two‐step computational framework with 3‐fold validation that first identified dissociation constant as a reliable predictor of binding affinity in hetero‐ dimeric and trimeric protein complexes. The second step implements dissociation constant as descriptor of the binding strengths of SARS‐CoV‐2 variants RBD to hACE2 and NAbs. Then, we examined several variants of concerns (VOCs) such as Alpha, Beta, Gamma, Delta, and Omicron and demonstrated that these VOCs RBD bind to the hACE2 with enhanced affinity. Furthermore, the binding affinity of Omicron variant's RBD was reduced with majority of the RBD‐directed NAbs, which is highly consistent with the experimental neutralization data. By studying the atomic contacts between RBD and NAbs, we revealed the molecular footprints of four NAbs (GH‐12, P2B‐1A1, Asarnow_3D11, and C118)—that may likely neutralize the recently emerged Omicron variant—facilitating enhanced binding affinity. Finally, our findings suggest a computational pathway that could aid researchers identify a range of current NAbs that may be effective against emerging SARS‐CoV‐2 variants.
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SciScore for 10.1101/2022.02.11.480177: (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 These multiple sequences were aligned by MAFFT [16] to extract the sequence fragment encoding for receptor-binding domain of spike protein (T333 – G526). MAFFTsuggested: (MAFFT, RRID:SCR_011811)) (ab initio and homology-based hybrid methodology) [24]; Modeller (version 10.1) Modellersuggested: (MODELLER, RRID:SCR_008395)We employed the standalone versions of PRODIGY [33] and PISA [34] on the most reliable RBD-hACE2 and RBD-NAbs complexes to estimate these distinct matrices. PISAsuggested: (PISA, RRID:SCR_015749)We employed MedCalc® statistical software version 20.026 to calculate weight … SciScore for 10.1101/2022.02.11.480177: (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 These multiple sequences were aligned by MAFFT [16] to extract the sequence fragment encoding for receptor-binding domain of spike protein (T333 – G526). MAFFTsuggested: (MAFFT, RRID:SCR_011811)) (ab initio and homology-based hybrid methodology) [24]; Modeller (version 10.1) Modellersuggested: (MODELLER, RRID:SCR_008395)We employed the standalone versions of PRODIGY [33] and PISA [34] on the most reliable RBD-hACE2 and RBD-NAbs complexes to estimate these distinct matrices. PISAsuggested: (PISA, RRID:SCR_015749)We employed MedCalc® statistical software version 20.026 to calculate weight Kappa statistic. MedCalc®suggested: (MedCalc, RRID:SCR_015044)The graphs were generated using GraphPad Prism 7.01 (GraphPad Software, San Diego, CA). GraphPadsuggested: (GraphPad Prism, RRID:SCR_002798)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.
Results from scite Reference Check: We found no unreliable references.
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