Modelling conformational state dynamics and its role on infection for SARS-CoV-2 Spike protein variants

Teruel, Natália; Mailhot, Olivier; Najmanovich, Rafaël

doi:10.1101/2020.12.16.423118

Cited by 27 publications

(34 citation statements)

References 64 publications

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“…This observation indicated that the D614G mutant may perturb hinge clusters and alter functional movements in the closed S-RRARS trimer, potentially priming protomers in the S protein for transition to the open form. These findings showed an agreement with previous studies suggesting the increase in the open state preferences for the D614G mutation due to the increased flexibility of the closed state and the enhanced rigidification of the open form 52. Indeed, while local conformational mobility profiles are similar for the native S-D614…”

supporting

confidence: 93%

“…It is worth noting that in agreement with several computational studies advocating for the "openness" mechanism 50 computational study. 52 Based on these preliminary results, we suggested a hypothesis that the D614G substitution may cause a cascade of small and subtle changes in both the intra-and…”

Section: Dynamic-based Modeling Of Residue Interaction Network and Comentioning

confidence: 85%

“…(Figure 2E, F). Several previous studies suggested that the molecular basis of the increased infectivity for the D614G mutant may be explained via "openness" hypothesis [50][51][52] according to which D614G modification can alter conformational dynamics signatures of the S protein and promote switching to the open conformation, positioning a single or multiple RBDs to make contacts with the ACE2 receptor.…”

Section: Dynamic-based Modeling Of Residue Interaction Network and Comentioning

confidence: 99%

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Computational Analysis of Protein Stability and Allosteric Interaction Networks in Distinct Conformational Forms of the SARS-CoV-2 Spike D614G Mutant: Reconciling Functional Mechanisms through Allosteric Model of Spike Regulation

Verkhivker

Agajanian

Oztas

et al. 2021

Preprint

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Structural and biochemical studies SARS-CoV-2 spike mutants with the enhanced infectivity have attracted significant attention and offered several mechanisms to explain the experimental data. The development of a unified view and a working model which is consistent with the diverse experimental data is an important focal point of the current work. In this study, we used an integrative computational approach to examine molecular mechanisms underlying functional effects of the D614G mutation by exploring atomistic modeling of the SARS-CoV-2 spike proteins as allosteric regulatory machines. We combined coarse-grained simulations, protein stability and dynamic fluctuation communication analysis along with network-based community analysis to simulate structures of the native and mutant SARS-CoV-2 spike proteins in different functional states. The results demonstrated that the D614 position anchors a key regulatory cluster that dictates functional transitions between open and closed states. Using molecular simulations and mutational sensitivity analysis of the SARS-CoV-2 spike proteins we showed that the D614G mutation can improve stability of the spike protein in both closed and open forms, but shifting thermodynamic preferences towards the open mutant form. The results offer support to the reduced shedding mechanism of S1 domain as a driver of the increased infectivity triggered by the D614G mutation. Through distance fluctuations communication analysis, we probed stability and allosteric communication propensities of protein residues in the native and mutant SARS-CoV-2 spike proteins, providing evidence that the D614G mutation can enhance long-range signaling of the allosteric spike engine. By employing network community analysis of the SARS-CoV-2 spike proteins, our results revealed that the D614G mutation can promote the increased number of stable communities and allosteric hub centers in the open form by reorganizing and enhancing the stability of the S1-S2 inter-domain interactions and restricting mobility of the S1 regions. This study provides atomistic-based view of the allosteric interactions and communications in the SARS-CoV-2 spike proteins, suggesting that the D614G mutation can exert its primary effect through allosterically induced changes on stability and communications in the residue interaction networks.

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supporting

confidence: 93%

Section: Dynamic-based Modeling Of Residue Interaction Network and Comentioning

confidence: 85%

Section: Dynamic-based Modeling Of Residue Interaction Network and Comentioning

confidence: 99%

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Computational Analysis of Protein Stability and Allosteric Interaction Networks in Distinct Conformational Forms of the SARS-CoV-2 Spike D614G Mutant: Reconciling Functional Mechanisms through Allosteric Model of Spike Regulation

Verkhivker

Agajanian

Oztas

et al. 2021

Preprint

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“…96 Coarse-grained normal mode analyses combined with Markov model and computation of transition probabilities characterized the dynamics of the S protein and the effects of mutational variants D614G and N501Y on protein dynamics and energetics. 97 Using time-independent component analysis (tICA) and protein networks, another computational study identified the hotspot residues that may exhibit long-distance coupling with the RBD opening, showing that some mutations may allosterically affect the stability of the RBD regions. 98…”

Section: Sars-cov-2 S Protein Between a Spectrum Of Closed And Receptmentioning

confidence: 99%

Comparative Perturbation-Based Modeling of the SARS-CoV-2 Spike Protein Binding with Host Receptor and Neutralizing Antibodies : Structurally Adaptable Allosteric Communication Hotspots Define Spike Sites Targeted by Global Circulating Mutations

Verkhivker

Agajanian

Oztas

et al. 2021

Preprint

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In this study, we used an integrative computational approach focused on comparative perturbation-based modeling to examine molecular mechanisms and determine functional signatures underlying role of functional residues in the SARS-CoV-2 spike protein that are targeted by novel mutational variants and antibody-escaping mutations. Atomistic simulations and functional dynamics analysis are combined with alanine scanning and mutational sensitivity profiling for the SARS-CoV-2 spike protein complexes with the ACE2 host receptor are REGN-COV2 antibody cocktail (REG10987+REG10933). Using alanine scanning and mutational sensitivity analysis, we have shown that K417, E484 and N501 residues correspond to key interacting centers with a significant degree of structural and energetic plasticity that allow mutants in these positions to afford the improved binding affinity with ACE2. Through perturbation-based network modeling and community analysis of the SARS-CoV-2 spike protein complexes with ACE2 we demonstrate that E406, N439, K417 and N501 residues serve as effector centers of allosteric interactions and anchor major inter-molecular communities that mediate long-range communication in the complexes. The results provide support to a model according to which mutational variants and antibody-escaping mutations constrained by the requirements for host receptor binding and preservation of stability may preferentially select structurally plastic and energetically adaptable allosteric centers to differentially modulate collective motions and allosteric interactions in the complexes with the ACE2 enzyme and REGN-COV2 antibody combination. This study suggests that SARS-CoV-2 spike protein may function as a versatile and functionally adaptable allosteric machine that exploits plasticity of allosteric regulatory centers to fine-tune response to antibody binding without compromising activity of the spike protein.

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“…In the case of B.1.1.7, a series of mutations in eight sites including D614G appeared in the spike protein: ∆69∆70, ∆144∆145, N501Y, A570D, P681H, T716I, S982A, and D1118H (https://www.gisaid.org; GISAID, accessed on 1 December 2020). Among them, ∆69∆70 and N501Y in B.1.1.7 lineage have been shown to cause a conformational change in the spike protein and have higher infectivity than D614G, suggesting that they may increase transmissibility and alter antigenicity [10,11]. Remarkably, B.1.351 contains additional two mutations, K417N and E484K, in receptor binding motif (RBM) of the RBD region and those may potentially induce a conformational change of the spike protein, and subsequently increase the infectivity of B.1.351 than other lineages.…”

Section: Introductionmentioning

confidence: 99%

The Impact on Infectivity and Neutralization Efficiency of SARS-CoV-2 Lineage B.1.351 Pseudovirus

Kim

Jang

Soh

et al. 2021

Viruses

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A new variant of SARS-CoV-2 B.1.351 lineage (first found in South Africa) has been raising global concern due to its harboring of multiple mutations in the spike that potentially increase transmissibility and yield resistance to neutralizing antibodies. We here tested infectivity and neutralization efficiency of SARS-CoV-2 spike pseudoviruses bearing particular mutations of the receptor-binding domain (RBD) derived either from the Wuhan strains (referred to as D614G or with other sites) or the B.1.351 lineage (referred to as N501Y, K417N, and E484K). The three different pseudoviruses B.1.351 lineage related significantly increased infectivity compared with other mutants that indicated Wuhan strains. Interestingly, K417N and E484K mutations dramatically enhanced cell–cell fusion than N501Y even though their infectivity were similar, suggesting that K417N and E484K mutations harboring SARS-CoV-2 variant might be more transmissible than N501Y mutation containing SARS-CoV-2 variant. We also investigated the efficacy of two different monoclonal antibodies, Casirivimab and Imdevimab that neutralized SARS-CoV-2, against several kinds of pseudoviruses which indicated Wuhan or B.1.351 lineage. Remarkably, Imdevimab effectively neutralized B.1.351 lineage pseudoviruses containing N501Y, K417N, and E484K mutations, while Casirivimab partially affected them. Overall, our results underscore the importance of B.1.351 lineage SARS-CoV-2 in the viral spread and its implication for antibody efficacy.

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Modelling conformational state dynamics and its role on infection for SARS-CoV-2 Spike protein variants

Cited by 27 publications

References 64 publications

Computational Analysis of Protein Stability and Allosteric Interaction Networks in Distinct Conformational Forms of the SARS-CoV-2 Spike D614G Mutant: Reconciling Functional Mechanisms through Allosteric Model of Spike Regulation

Computational Analysis of Protein Stability and Allosteric Interaction Networks in Distinct Conformational Forms of the SARS-CoV-2 Spike D614G Mutant: Reconciling Functional Mechanisms through Allosteric Model of Spike Regulation

Comparative Perturbation-Based Modeling of the SARS-CoV-2 Spike Protein Binding with Host Receptor and Neutralizing Antibodies : Structurally Adaptable Allosteric Communication Hotspots Define Spike Sites Targeted by Global Circulating Mutations

The Impact on Infectivity and Neutralization Efficiency of SARS-CoV-2 Lineage B.1.351 Pseudovirus

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