Towards an optimal monoclonal antibody with higher binding affinity to the receptor-binding domain of SARS-CoV-2 spike proteins from different variants

  1. Andrei Neamtu
  2. Francesca Mocci
  3. Aatto Laaksonen
  4. Fernando L. Barroso da Silva

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Abstract

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  1. Version published to 10.1016/j.colsurfb.2022.112986
  2. ScreenIT

    SciScore for 10.1101/2022.01.04.474958: (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

    Antibodies
    SentencesResources
    To study the molecular mechanisms in SARS-CoV-2 S protein binding with several Abs, Verkhivker and Di Paola (Verkhivker and Di Paola, 2021) performed all-atom and CG simulations with mutational sensitivity mapping using the BeAtMuSiC approach and perturbation response scanning (PRS) profiling of SARS-CoV-2 receptor-binding domain complexed with CR3022 and CB6 antibodies, complementing it with a network modeling analysis of the residue interactions.
    CB6
    suggested: None
    They have included the complexes between the RBD of SARS-CoV-2 spike (S) glycoprotein and CR3022 or S309 antibodies and the ACE2 receptor.
    S309
    suggested: None
    Each outer cycle consists of randomly choosing CDRs (L1, L2, L3, H1, H2, H3) from clusters in the RAbD database and then grafting that CDR’s structure onto the antibody framework in place of the existing CDRs (GraftDesign).
    L3
    suggested: None
    Considering that any antibody has 6 CDR’s (i.e. L1, L2, L3 on the light chain and H1, H2, H3 on the heavy chain) one has to decide which of these CDR’s should be modified with respect to the original structure (CR3022 as given by PDB id 6w41).
    L1
    suggested: None
    L2
    suggested: None
    H1
    suggested: None
    H2
    suggested: None
    L1 in the original CR3022 antibody is an extended loop that makes a large surface area contact with the RBD antigen (wildtype/Wuhan sequence) which stabilizes the Ab-Ag interaction.
    CR3022
    suggested: None
    Different studies have highlighted the importance of these interactions for the host-pathogen and antigen-specific antibody interfaces (Bai and Warshel, 2020; Corrêa Giron et al., 2020; Nguyen et al., 2021, 2020; Poveda-Cuevas et al., 2020, 2018; Xie et al., 2021).
    antigen-specific
    suggested: (Miltenyi Biotec Cat# 130-092-104, RRID:AB_615063)
    Software and Algorithms
    SentencesResources
    The GROMACS 2019.3 suite (Abraham et al., 2015) has been used for all atomistic MD simulations.
    GROMACS
    suggested: (GROMACS, RRID:SCR_014565)

    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:
    Considering that any computational method has its limitations and accuracy, evaluating the Ab-Ag complexes with complementary computational approaches, and selecting the ones that are consistent in all evaluations, strongly increase the reliability of predictions. Thus, the observed improved affinity of the models could be considered to result from the real physics/chemistry of the complex interactions in the systems and not from any particular algorithm-related issues. RBD-Ab free energy of interactions explored with umbrella sampling CG simulations: Free energy calculations using US MD calculations revealed that from the list of the top 10 best RAbD candidates only P01, P05, P06, P09, and P10 showed better binding affinities compared with the native CR3022 (see Figure 5 for their PMF profiles). Although all these candidates show statistically significant improved affinities compared with CR3022, the errors in estimating the binding free energies for P05, P06, P09, and P10 did not allow us to distinguish between them in terms of affinity. Among the candidates P01 seems the best, giving statistically significant better affinity of binding compared with both the native CR3022 and the P05, P06, P09, and P10 set. However, caution must be taken when considering absolute values obtained by US-CG SIRAH to compare with more rigorous atomistic or experimental data. As the results of Patel et al. (2017) showed, only the ΔΔG = ΔGmutant -ΔGwild-type should be regarded quantitatively, as...

    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.

    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.

  3. Version published to 10.1101/2022.01.04.474958v1 on bioRxiv