A rigorous framework for detecting SARS-CoV-2 spike protein mutational ensemble from genomic and structural features

Fatihi, Saman; Rathore, Surabhi; Pathak, Ankit Kumar; Gahlot, Deepanshi; Mukerji, Mitali; Jatana, Nidhi; Thukral, Lipi

doi:10.1101/2021.02.17.431625

Cited by 3 publications

(3 citation statements)

References 91 publications

(75 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…2020). Detailed modelling methodology is mentioned in our previous work (Fatihi et al, 2021). The structural mutant model of B.1.617.2 variant was generated using the structural model of ACE2-bound 1 RBD-up spike conformation as a reference.…”

Section: Protein Annotation and Modellingmentioning

confidence: 99%

Genomic characterization and Epidemiology of an emerging SARS-CoV-2 variant in Delhi, India

Dhar

Marwal

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

In April 2021, after successfully enduring three waves of the SARS-CoV2 pandemic in 2020, and having reached population seropositivity of about 50%, Delhi, the national capital of India was overwhelmed by the fourth wave. Here, we trace viral, host, and social factors contributing to the scale and exponent of the fourth wave, when compared to preceding waves, in an epidemiological context. Genomic surveillance data from Delhi and surrounding states shows an early phase of the upsurge driven by the entry of the more transmissible B.1.1.7 variant of concern (VOC) into the region in January, with at least one B.1.1.7 super spreader event in February 2021, relatable to known mass gatherings over this period. This was followed by seeding of the B.1.617 VOC, which too is highly transmissible, with rapid expansion of B.1.617.2 sub-lineage outpacing all other lineages. This unprecedented growth of cases occurred in the background of high seropositivity, but with low median neutralizing antibody levels, in a serially sampled cohort. Vaccination breakthrough cases over this period were noted, disproportionately related to VOC in sequenced cases, but usually mild. We find that this surge of SARS-CoV2 infections in Delhi is best explained by the introduction of a new highly transmissible VOC, B.1.617.2, with likely immune-evasion properties; insufficient neutralizing immunity, despite high seropositivity; and social behavior that promoted transmission.

show abstract

Section: Protein Annotation and Modellingmentioning

confidence: 99%

Genomic characterization and Epidemiology of an emerging SARS-CoV-2 variant in Delhi, India

Dhar

Marwal

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…The crystal structure of different human neutralizing monoclonal antibodies CR3022 6W41 20 , B38 7BZ5 21 , CB6 7C01 22 , P2B-2F6 7BWJ 23 ,and REGN 6XDG 24 were retrieved from PDB RCSB database. In addition, the crystal structure of the hACE2 receptor (PDB ID: 7A97) and S protein (7AD1) was also retrieved 25 .…”

Section: Data Setsmentioning

confidence: 99%

The influence of new SARS-CoV-2 variant Omicron (B.1.1.529) on vaccine efficacy, its correlation to Delta Variants: a computational approach

Ranjan

Neha

Devi

et al. 2021

Preprint

View full text Add to dashboard Cite

The newly discovered COVID variant B.1.1.529 in Botswana has more than 30 mutations in spike and many other in non-spike proteins, far more than any other SARS-CoV-2 variant accepted as a variant of concern by the WHO and officially named Omicron, and has sparked concern among scientists and the general public. Our findings provide insights into structural modification caused by the mutations in the Omicrons receptor-binding domain and look into the effects on interaction with the hosts neutralising antibodies CR3022, B38, CB6, P2B-2F6, and REGN, as well as ACE2R using an in silico approach. We have employed secondary structure prediction, structural superimposition, protein disorderness, molecular docking, and MD simulation to investigate host-pathogen interactions, immune evasion, and transmissibility caused by mutations in the RBD region of the spike protein of the Omicron variant and compared it to the Delta variants (AY.1, AY.2, & AY.3) and wild type. Computational analysis revealed that the Omicron variant has a higher binding affinity for the human ACE2 receptor than the wild and Delta (AY.1 and AY.2 strains), but lower than the Delta AY.3 strain. MD simulation and docking analysis suggest that the omicron and Delta AY.3 were found to have relatively unstable and compact RBD structures and hampered interactions with antibodies more than wild and Delta (AY.1 and AY.2), which may lead to relatively more pathogenicity and antibody escape. In addition, we observed lower binding affinity of Omicron for human monoclonal antibodies (CR3022, B38, CB6, and P2B2F6) when compared to wild and Delta (AY.1 & AY.2). However, the binding affinity of Omicron RBD variants for CR3022, B38, and P2B2F6 antibodies is lower as compared to Delta AY.3, which might promote immune evasion and reinfection and needs further experimental investigation.

show abstract

“…67 The multiscale structural modeling and atomistic molecular dynamics (MD) simulations of the full-length SARS-CoV-2 S glycoprotein embedded in the viral membrane, with a complete glycosylation profile provided the blueprint for biophysical modeling of S proteins. [68][69][70][71][72][73][74] Using deep data analysis and protein structure network modeling of MD simulations, another computational study identified residues that exhibit long-distance coupling with the RBD opening, including sites harboring functional mutations D614G and A570D which points to the important role of D614G variant in modulating allosteric communications in the S protein. 75 The free energy landscapes of the S protein derived from MD simulations together with nudged elastic pathway optimization mapping of the RBD opening revealed a specific transient allosteric pocket at the hinge region that is located near D614 position influences RBD dynamics.…”

Section: Introductionmentioning

confidence: 99%

The Landscape-Based Protein Stability Analysis and Network Modeling of Multiple Conformational States of the SARS-CoV-2 Spike D614 Mutant: Conformational Plasticity and Frustration-Driven Allostery as Energetic Drivers of Highly Transmissible Spike Variant

Verkhivker

Agajanian

Kassab

et al. 2021

Preprint

View full text Add to dashboard Cite

The structural and functional studies of the SARS-CoV-2 spike protein variants revealed an important role of the D614G mutation that is shared across many variants of concern(VOCs), suggesting the effect of this mutation on the enhanced virus infectivity and transmissibility. The recent structural and biophysical studies provided important evidence about multiple conformational substates of the D614G spike protein. The development of a plausible mechanistic model which can explain the experimental observations from a more unified thermodynamic perspective is an important objective of the current work. In this study, we employed efficient and accurate coarse-grained simulations of multiple structural substates of the D614G spike trimers together with the ensemble-based mutational frustration analysis to characterize the dynamics signatures of the conformational landscapes. By combining the local frustration profiling of the conformational states with residue-based mutational scanning of protein stability and network analysis of allosteric interactions and communications, we determine the patterns of mutational sensitivity in the functional regions and sites of variants. We found that the D614G mutation may induce a considerable conformational adaptability of the open states in the SARS-CoV-2 spike protein without compromising folding stability and integrity of the spike protein. The results suggest that the D614G mutant may employ a hinge-shift mechanism in which the dynamic couplings between the site of mutation and the inter-protomer hinge modulate the inter-domain interactions, global mobility change and the increased stability of the open form. This study proposes that mutation-induced modulation of the conformational flexibility and energetic frustration at the inter-protomer interfaces may serve as an efficient mechanism for allosteric regulation of the SARS-CoV-2 spike proteins.

show abstract

A rigorous framework for detecting SARS-CoV-2 spike protein mutational ensemble from genomic and structural features

Cited by 3 publications

References 91 publications

Genomic characterization and Epidemiology of an emerging SARS-CoV-2 variant in Delhi, India

Genomic characterization and Epidemiology of an emerging SARS-CoV-2 variant in Delhi, India

The influence of new SARS-CoV-2 variant Omicron (B.1.1.529) on vaccine efficacy, its correlation to Delta Variants: a computational approach

The Landscape-Based Protein Stability Analysis and Network Modeling of Multiple Conformational States of the SARS-CoV-2 Spike D614 Mutant: Conformational Plasticity and Frustration-Driven Allostery as Energetic Drivers of Highly Transmissible Spike Variant

Contact Info

Product

Resources

About