Atomistic Simulations and In Silico Mutational Profiling of Protein Stability and Binding in the SARS-CoV-2 Spike Protein Complexes with Nanobodies: Molecular Determinants of Mutational Escape Mechanisms
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SciScore for 10.1101/2021.07.07.451538: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
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Antibodies Sentences Resources Structure Preparation and Analysis: The cryo-EM structures of SARS-CoV-2 S proteins used in this study included the S-RBD complex with ACE2 (pdb id 6M0J), and crystal structures of the SARS-CoV-2 S-RBD complexes with a series of highly potent neutralizing nanobodies and various nanobody cocktails including Nb6 (pdb id 7KKKJ), Nb20 (pdb 7JVB), VHH E (pdb id 7B14), a nanobody combination pair VHH E/ VHH U (pdb id 7KN5), biparatopic nanobody VHH VE (pdb id 7B17), as well as antibody/nanobody cocktails such as combination of CC12.3 antibody and VHH V nanobody (pdb id 7KN6), and combination of CC12.3 … SciScore for 10.1101/2021.07.07.451538: (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 Sentences Resources Structure Preparation and Analysis: The cryo-EM structures of SARS-CoV-2 S proteins used in this study included the S-RBD complex with ACE2 (pdb id 6M0J), and crystal structures of the SARS-CoV-2 S-RBD complexes with a series of highly potent neutralizing nanobodies and various nanobody cocktails including Nb6 (pdb id 7KKKJ), Nb20 (pdb 7JVB), VHH E (pdb id 7B14), a nanobody combination pair VHH E/ VHH U (pdb id 7KN5), biparatopic nanobody VHH VE (pdb id 7B17), as well as antibody/nanobody cocktails such as combination of CC12.3 antibody and VHH V nanobody (pdb id 7KN6), and combination of CC12.3 antibody and VHH W nanobody (pdb id 7KN7) (Figure 1). ACE2suggested: NoneNb20suggested: (Millipore Cat# NB20-100UG, RRID:AB_213193)Software and Algorithms Sentences Resources All-atom MD simulations were performed for an N, P, T ensemble in explicit solvent using NAMD 2.13 package101 with CHARMM36 force field. NAMDsuggested: (NAMD, RRID:SCR_014894)We performed principal component analysis (PCA) of reconstructed trajectories derived from CABS-CG simulations using the CARMA package106 and also determined the essential slow mode profiles using elastic network models (ENM) analysis.107–109 Two elastic network models: Gaussian network model (GNM) and Anisotropic network model (ANM) approaches were used to compute the amplitudes of isotropic thermal motions and directionality of anisotropic motions. CARMAsuggested: (CARMA, RRID:SCR_004999)Results from OddPub: Thank you for sharing your data.
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:In this analysis, positive folding free energy contributions are suggestive of stability weaknesses sites and negative folding free energies point to the structurally stable positions in the S-RBD. We first analyzed the mutational profiles for the S-RBD complexes with Nb6 and Nb20 nanobodies (Figure 4). Mutational sensitivity analysis of the S-RBD binding with Nb6 showed that a significant fraction of the epitope residues can contribute to the binding affinity, suggesting that the nanobody interactions with the ACE2-binding site may be highly efficient (Figure 4A). The key binding energy hotspots for Nb6 corresponded to the hydrophobic residues Y449, L453, L455, F456, G485, Y489, F490, G496 and Y505 (Figure 4A,B). A number of these positions are recognized as important binding affinity hotspots for ACE2 as evident from deep mutagenesis scanning of SARS-CoV-2 interactions with the ACE2 host receptor.39 The interaction pattern and similarity in the binding energy hotspots with ACE2 supported the notion of structural mimicry that may be efficiently exploited by Nb6 nanobody to competitively inhibit the ACE binding region. The folding free energies of the S-RBD residues reflected high stability of the conserved core of the S-RBD consisting of antiparallel β strands (β1 to β4 and β7) (residues 354-358, 376-380, 394-403, 431-438, 507-516) and also pointed to a moderate stabilization of β5 and β6 (residues 451-454 and 492-495) that link the binding region to the central core (Figure...
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: Please consider improving the rainbow (“jet”) colormap(s) used on pages 65, 10, 11, 63, 22, 60, 61 and 31. At least one figure is not accessible to readers with colorblindness and/or is not true to the data, i.e. not perceptually uniform.
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Results from scite Reference Check: We found no unreliable references.
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