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Comparative structural analyses of selected spike protein-RBD mutations in SARS-CoV-2 lineages.

ABSTRACT: The severity of COVID-19 has been observed throughout the world as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) globally claimed more than 2 million lives and left a devastating impact worldwide. Recently several virulent mutant strains of this virus, such as the B.1.1.7, B.1.351, and P1 lineages, have emerged with initial predominance in UK, South Africa, and Brazil. Another extremely pathogenic B.1.617 lineage and its sub-lineages, first detected in India, are now affecting some countries at notably stronger spread-rates. The present paper computationally examines the time-based structures of B.1.1.7, B.1.351, and P1 lineages with selected spike protein mutations. The mutations in the more recently found B.1.617 lineage and its sub-lineages are explored, and the implications for multiple point mutations of the spike protein's receptor-binding domain (RBD) are described. The selected S1 mutations within the highly contagious B.1.617.2 sub-lineage, also known as the delta variant, are examined as well.

SUBMITTER: Roy U

PROVIDER: S-EPMC8592829 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Comparative structural analyses of selected spike protein-RBD mutations in SARS-CoV-2 lineages.

Roy Urmi U

Immunologic research 20211116 2

The severity of COVID-19 has been observed throughout the world as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) globally claimed more than 2 million lives and left a devastating impact worldwide. Recently several virulent mutant strains of this virus, such as the B.1.1.7, B.1.351, and P1 lineages, have emerged with initial predominance in UK, South Africa, and Brazil. Another extremely pathogenic B.1.617 lineage and its sub-lineages, first detected in India, are now affecting som ...[more]

PMID: 34782989

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Project description:BackgroundA large number of mutations in the Spike (S) protein of the SARS-CoV-2 omicron variant have been noted to alter the receptor binding domain (RBD) and increase the binding surface and enhance the opening of the binding pocket. The cumulative effect of S1 and S2 subunit mutations can influence the conformational dynamics of the binding surface, facilitating the release of viral genome into host cells.AimThis study investigates the deleterious mutations across all Omicron lineages identified in our analysis and their effect on the conformational stability of RBD opening.MethodsWhole Genome Sequencing of 231 SARS-CoV-2 positive patients in Karachi, Pakistan, were performed using Illumina Miseq instrument and raw reads were analyzed using viralrecon pipeline. The mutational effects of omicron variant on the stability of S protein, including wild-type (7FG7), close (6VXX) and open (6VYB) states, were assessed through MD simulations.ResultsFour deleterious missense mutations (Tyr505His, Asn764Lys, Asp950Asn, Asn969Lys) were identified in the S1 and S2 subunit of the S protein of omicron variant. In the wildtype and open state mutant models, Tyr505His, Asp950Asn and Asn969Lys caused destabilizing effects, higher RMSDs vs. wild-type, and fluctuations in the RBD (438-510) region and S2 subunit (946-1010), compared to the native structure. These mutations increased the binding pocket propensity to open in mutant model compared to the native open conformation (6VYB). This structural change promoted trimer opening in the open state through α-helix movement in the S2 subunit away from the RBD region. In the closed state, only S2 subunit mutations (Asp950Asn and Asn969Lys) lead to predicted destabilization through the movement of protomer C towards protomer B (RBD region). These S2 subunit mutations are predicted to stabilize the RBD "down" conformation potentially enhancing spike antigenic heterogeneity.ConclusionThis study highlighted the cumulative effect of S1 (Tyr505His) and S2 (Asp950Asn and Asn969Lys) subunits mutations on different S protein states, potentially controlling its conformational dynamics and presentation to host receptors. Future experimental studies are needed to elucidate the biological significance of these alterations, particularly by establishing a link between the identified mutations and their impact on viral biology.

Project description:Coronavirus Disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly spread around the world jeopardizing the global economy and health. The rapid proliferation and infectivity of the virus can be attributed to many accumulating mutations in the spike protein leading to continuous generation of variants. The spike protein is a glycoprotein that recognizes and binds to cell surface receptor known as angiotensin-converting enzyme 2 (ACE2) leading to the fusion of the viral and host cell membranes and entry into the host cells. These circulating variants in the population have greatly impacted the virulence, transmissibility, and immunological evasion of the host. The present study is aimed at understanding the impact of the major mutations (L452R, T478K and N501Y) in the receptor-binding domain (RBD) of spike protein and their consequences on the binding affinity to human ACE2 through protein-protein docking and molecular dynamics simulation approaches. Protein-protein docking and Molecular mechanics with generalised Born and surface area solvation (MM/GBSA) binding free energy analysis reveal that the spike mutants-L452R, T478K and N501Y have a higher binding affinity to human ACE2 as compared to the native spike protein. The increase in the number of interface residues, interface area and intermolecular forces such as hydrogen bonds, salt bridges and non-bonded contacts corroborated with the increase in the binding affinity of the spike mutants to ACE2. Further, 75 ns all-atom molecular dynamics simulation investigations show variations in the geometric properties such as root mean square deviation (RMSD), radius of gyration (Rg), total solvent accessible surface area (SASA) and number of hydrogen bonds (NHBs) in the mutant spike:ACE2 complexes with respect to the native spike:ACE2 complex. Therefore, the findings of this study unravel plausible molecular mechanisms of increase in binding affinity of spike mutants (L452R, T478K and N501Y) to human ACE2 leading to higher virulence and infectivity of emerging SARS-CoV-2 variants. The study will further aid in designing novel therapeutics targeting the interface residues between spike protein and ACE2 receptor.

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Comparative structural analyses of selected spike protein-RBD mutations in SARS-CoV-2 lineages.

Publications

Comparative structural analyses of selected spike protein-RBD mutations in SARS-CoV-2 lineages.

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