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

AbstractThe recent release of SARS-CoV-2 genomic data from several countries has provided clues into the potential antigenic drift of the coronavirus population. In particular, the genomic instability observed in the spike protein necessitates immediate action and further exploration in the context of viral-host interactions. Here we dynamically track 3,11,795 genome sequences of spike protein, which comprises 2,584 protein mutations. We reveal mutational genomic ensemble at different timing and geographies, that evolves on four distinct residues. In addition to the well-established N501 mutational cluster, we detect the presence of three novel clusters, namely A222, N439, and S477. The robust examination of structural features from 44 known cryo-EM structures showed that the virus is deploying many mutations within these clusters on structurally heterogeneous regions. One such dominant variant D614G was also simulated using molecular dynamics simulations and, as compared to wild-type, we found higher stability with human ACE2 receptor. There is also a significant overlap of mutational clusters on known epitopes, indicating putative interference with antibody binding. Thus, we propose that the resulting coaxility of mutational clusters is the most efficient feature of SARS-CoV-2 evolution and provides precise mutant combinations that can enable future vaccine re-positioning.

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Inhibitor potency varies widely among tumor-relevant human isocitrate dehydrogenase 1 mutants

Biochemical Journal ◽

10.1042/bcj20180424 ◽

2018 ◽

Vol 475 (20) ◽

pp. 3221-3238 ◽

Cited By ~ 4

Author(s):

Diego Avellaneda Matteo ◽

Grace A. Wells ◽

Lucas A. Luna ◽

Adam J. Grunseth ◽

Olga Zagnitko ◽

...

Keyword(s):

Isocitrate Dehydrogenase ◽

Resistance Mutation ◽

Poor Response ◽

Fold Increase ◽

Structural Features ◽

Low Grade ◽

Wild Type ◽

Isocitrate Dehydrogenase 1 ◽

Dynamics Simulations ◽

Mutant Idh1

Mutations in isocitrate dehydrogenase 1 (IDH1) drive most low-grade gliomas and secondary glioblastomas and many chondrosarcomas and acute myeloid leukemia cases. Most tumor-relevant IDH1 mutations are deficient in the normal oxidization of isocitrate to α-ketoglutarate (αKG), but gain the neomorphic activity of reducing αKG to D-2-hydroxyglutarate (D2HG), which drives tumorigenesis. We found previously that IDH1 mutants exhibit one of two reactivities: deficient αKG and moderate D2HG production (including commonly observed R132H and R132C) or moderate αKG and high D2HG production (R132Q). Here, we identify a third type of reactivity, deficient αKG and high D2HG production (R132L). We show that R132Q IDH1 has unique structural features and distinct reactivities towards mutant IDH1 inhibitors. Biochemical and cell-based assays demonstrate that while most tumor-relevant mutations were effectively inhibited by mutant IDH1 inhibitors, R132Q IDH1 had up to a 16 300-fold increase in IC50 versus R132H IDH1. Only compounds that inhibited wild-type (WT) IDH1 were effective against R132Q. This suggests that patients with a R132Q mutation may have a poor response to mutant IDH1 therapies. Molecular dynamics simulations revealed that near the NADP+/NADPH-binding site in R132Q IDH1, a pair of α-helices switches between conformations that are more wild-type-like or more mutant-like, highlighting mechanisms for preserved WT activity. Dihedral angle changes in the dimer interface and buried surface area charges highlight possible mechanisms for loss of inhibitor affinity against R132Q. This work provides a platform for predicting a patient's therapeutic response and identifies a potential resistance mutation that may arise upon treatment with mutant IDH inhibitors.

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Inferring the stabilization effects of SARS-CoV-2 variants on the binding with ACE2 receptor

10.1101/2021.04.18.440345 ◽

2021 ◽

Author(s):

Mattia Miotto ◽

Lorenzo Di Rienzo ◽

Giorgio Gosti ◽

Leonardo Bo ◽

Giacomo Parisi ◽

...

Keyword(s):

Control Systems ◽

South African ◽

Negative Control ◽

Spike Protein ◽

Special Focus ◽

Wild Type ◽

Shape Complementarity ◽

The Stability ◽

The Moment ◽

Dynamics Simulations

With the progression of the SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) pandemic, several variants of the virus are emerging with mutations distributed all over the viral sequence. While most of them are expected to have little to no effects at the phenotype level, some of these variants presenting specific mutations on the Spike protein are rapidly spreading, making urgent the need of characterizing their effects on phenotype features like contagiousness and antigenicity. With this aim, we performed extensive molecular dynamics simulations on a selected set of possible Spike variants in order to assess the stabilizing effect of particular amino acid substitutions, with a special focus on the mutations that are both characteristic of the top three most worrying variants at the moment, i.e the English, South African and Amazonian ones, and that occur at the molecular interface between SARS-CoV-2 Spike protein and its human ACE2 receptor. We characterize these variants' effect in terms of (i) residues mobility, (ii) compactness, studying the network of interactions at the interface, and (iii) variation of shape complementarity via expanding the molecular surfaces in the Zernike basis. Overall, our analyses highlighted greater stability of the three variant complexes with respect to both the wild type and two negative control systems, especially for the English and Amazonian variants. In addition, in the three variants, we investigate the effects a not-yet observed mutation in position 501 could provoke on complex stability. We found that a phenylalanine mutation behaves similarly to the English variant and may cooperate in further increasing the stability of the South African one, hinting at the need for careful surveillance for the emergence of such kind of mutations in the population. Ultimately, we show that the observables we propose describe key features for the stability of the ACE2-spike complex and can help to monitor further possible spike variants.

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Cold and distant: structural features of the nucleoprotein complex of a cold-adapted influenza A virus strain

10.1101/847608 ◽

2019 ◽

Author(s):

A.V. Shvetsov ◽

D.V. Lebedev ◽

Y.A. Zabrodskaya ◽

A.A. Shaldzhyan ◽

M.A. Egorova ◽

...

Keyword(s):

Primary Structure ◽

Cold Adaptation ◽

Influenza A ◽

Complex Function ◽

Structural Features ◽

Particle Model ◽

Wild Type ◽

Significant Difference ◽

Nucleoprotein Complex ◽

Dynamics Simulations

AbstractTwo influenza A nucleoprotein variants (wt: G102R; and mutant: G102R and E292G) were studied with regard to macro-molecular interactions in oligomeric form (24-mers). The E292G mutation has been previously shown to provide cold adaptation. Molecular dynamics simulations of these complexes and trajectory analysis showed that the most significant difference between the obtained models was distance differences between nucleoprotein complex strands. Influenza virus nucleoprotein complexes were isolated from strains bearing the corresponding NP amino acid substitutions. The isolated complexes were characterized by transmission electron microscopy and differential scanning fluorimetry (DSF). Presence of the E292G substitution was shown by DSF to affect nucleoprotein complex melting temperature. In the filament interface peptide model, it was shown that the peptide corresponding in primary structure to the wild-type NP (SGYDFEREGYS, wild type peptide) is prone to temperature-dependent self-association, unlike the peptide carrying the substitution corresponding to E292G (SGYDFGREGYS, mutant peptide). It was also shown that the SGYDFEREGYS peptide (wt) is capable of interacting with a recombinant full-size monomeric nucleoprotein (with primary structure corresponding to wild type); this interaction’s equilibrium dissociation constant is five orders of magnitude lower than for the SGYDFGREGYS peptide. Using small-angle neutron scattering (SANS), the supramolecular structures of isolated complexes of these proteins was studied at temperatures of 15, 32, and 37°C. SANS data show that the structures of the studied complexes (mutant or normal proteins with RNA) at elevated temperature differ from the rod-like particle model and react differently to temperature changes. The data suggest that the mechanism behind cold adaptation with E292G is associated with a weakening of the interaction between strands of the ribonucleoprotein complex and, as a result, the appearance of inter-chain interface flexibility necessary for complex function at low temperature.

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Inferring the stabilization effects of SARS-CoV-2 variants on the binding with ACE2 receptor

Communications Biology ◽

10.1038/s42003-021-02946-w ◽

2022 ◽

Vol 5 (1) ◽

Author(s):

Mattia Miotto ◽

Lorenzo Di Rienzo ◽

Giorgio Gosti ◽

Leonardo Bo’ ◽

Giacomo Parisi ◽

...

Keyword(s):

Control Systems ◽

South African ◽

Selective Advantage ◽

Negative Control ◽

Spike Protein ◽

Wild Type ◽

Shape Complementarity ◽

The Stability ◽

The Moment ◽

Dynamics Simulations

AbstractAs the SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) pandemic continues to spread, several variants of the virus, with mutations distributed all over the viral genome, are emerging. While most of the variants present mutations having little to no effects at the phenotypic level, some of these variants are spreading at a rate that suggests they may present a selective advantage. In particular, these rapidly spreading variants present specific mutations on the spike protein. These observations call for an urgent need to characterize the effects of these variants’ mutations on phenotype features like contagiousness and antigenicity. With this aim, we performed molecular dynamics simulations on a selected set of possible spike variants in order to assess the stabilizing effect of particular amino acid substitutions on the molecular complex. We specifically focused on the mutations that are both characteristic of the top three most worrying variants at the moment, i.e the English, South African, and Amazonian ones, and that occur at the molecular interface between SARS-CoV-2 spike protein and its human ACE2 receptor. We characterize these variants’ effect in terms of (i) residue mobility, (ii) compactness, studying the network of interactions at the interface, and (iii) variation of shape complementarity via expanding the molecular surfaces in the Zernike basis. Overall, our analyses highlighted greater stability of the three variant complexes with respect to both the wild type and two negative control systems, especially for the English and Amazonian variants. In addition, in the three variants, we investigate the effects a not-yet observed mutation in position 501 could provoke on complex stability. We found that a phenylalanine mutation behaves similarly to the English variant and may cooperate in further increasing the stability of the South African one, hinting at the need for careful surveillance for the emergence of these mutations in the population. Ultimately, we show that the proposed observables describe key features for the stability of the ACE2-spike complex and can help to monitor further possible spike variants.

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Scanning the RBD-ACE2 molecular interactions in Omicron variant

10.1101/2021.12.12.472253 ◽

2021 ◽

Author(s):

Soumya Lipsa Rath ◽

Aditya Kumar Padhi ◽

Nabanita Mandal

Keyword(s):

Molecular Basis ◽

Human Population ◽

Direct Interaction ◽

Spike Protein ◽

Amino Acid Substitutions ◽

Receptor Complex ◽

Receptor Binding Domain ◽

Wild Type ◽

Charge Dynamics ◽

Dynamics Simulations

The emergence of new SARS-CoV-2 variants poses a threat to the human population where it is difficult to assess the severity of a particular variant of the virus. Spike protein and specifically its receptor binding domain (RBD) which makes direct interaction with the ACE2 receptor of the human has shown prominent amino acid substitutions in most of the Variants of Concern. Here, by using all-atom molecular dynamics simulations we compare the interaction of Wild-type RBD/ACE2 receptor complex with that of the latest Omicron variant of the virus. We observed a very interesting diversification of the charge, dynamics and energetics of the protein complex formed upon mutations. These results would help us in understanding the molecular basis of binding of the Omicron variant with that of SARS-CoV-2 Wild-type.

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

Current Research in Structural Biology ◽

10.1016/j.crstbi.2021.11.002 ◽

2021 ◽

Author(s):

Saman Fatihi ◽

Surabhi Rathore ◽

Ankit K. Pathak ◽

Deepanshi Gahlot ◽

Mitali Mukerji ◽

...

Keyword(s):

Structural Features ◽

Spike Protein ◽

Rigorous Framework

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Cholesterol Transport in Wild-Type NPC1 and P691S: Molecular Dynamics Simulations Reveal Changes in Dynamical Behavior

International Journal of Molecular Sciences ◽

10.3390/ijms21082962 ◽

2020 ◽

Vol 21 (8) ◽

pp. 2962 ◽

Cited By ~ 3

Author(s):

Nadia Elghobashi-Meinhardt

Keyword(s):

Molecular Dynamics ◽

Dynamical Behavior ◽

Structural Data ◽

Md Simulations ◽

Structural Features ◽

Wild Type ◽

Lipid Storage Disease ◽

Signaling Mechanism ◽

Lipid Trafficking ◽

Dynamics Simulations

The Niemann–Pick C1 (NPC1) protein is the main protein involved in NPC disease, a fatal lysosomal lipid storage disease. NPC1, containing 1278 amino acids, is comprised of three lumenal domains (N-terminal, middle lumenal, C-terminal) and a transmembrane (TM) domain that contains a five helix bundle referred to as the sterol-sensing domain (SSD). The exact purpose of the SSD is not known, but it is believed that the SSD may bind cholesterol, either as a part of the lipid trafficking pathway or as part of a signaling mechanism. A recent cryo-EM structure has revealed an itraconazole binding site (IBS) in the SSD of human NPC1. Using this structural data, we constructed a model of cholesterol-bound wild-type (WT) and mutant P691S and performed molecular dynamics (MD) simulations of each cholesterol-bound protein. For WT NPC1, cholesterol migrates laterally, in the direction of the lipid bilayer. In the case of P691S, cholesterol is observed for the first time to migrate away from the SSD toward the N-terminal domain via a putative tunnel that connects the IBS with the lumenal domains. Structural features of the IBS are analyzed to identify the causes for different dynamical behavior between cholesterol-bound WT and cholesterol-bound P691S. The side chain of Ser691 in the P691S mutant introduces a hydrogen bond network that is not present in the WT protein. This change is likely responsible for the altered dynamical behavior observed in the P691S mutant and helps explain the disrupted cholesterol trafficking behavior observed in experiments.

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Structural and functional ramifications of antigenic drift in recent SARS-CoV-2 variants

Science ◽

10.1126/science.abh1139 ◽

2021 ◽

pp. eabh1139

Author(s):

Meng Yuan ◽

Deli Huang ◽

Chang-Chun D. Lee ◽

Nicholas C. Wu ◽

Abigail M. Jackson ◽

...

Keyword(s):

South Africa ◽

Binding Site ◽

Receptor Binding ◽

Neutralizing Antibodies ◽

Antigenic Drift ◽

Spike Protein ◽

Binding Modes ◽

Next Generation ◽

Wild Type ◽

Receptor Binding Site

Neutralizing antibodies (nAbs) elicited against the receptor-binding site (RBS) of the spike protein of wild-type SARS-CoV-2 are generally less effective against recent variants of concern. RBS residues E484, K417 and N501 are mutated in variants first described in South Africa (B.1.351) and Brazil (P.1). We analyzed their effects on ACE2 binding and K417N and E484K mutations on nAbs isolated from COVID-19 patients. Binding and neutralization of the two most frequently elicited antibody families (IGHV3-53/3-66 and IGHV1-2), which can both bind the RBS in alternate binding modes, are abrogated by K417N, E484K, or both. These effects can be structurally explained by their extensive interactions with RBS nAbs. However, nAbs to the more conserved, cross-neutralizing CR3022 and S309 sites were largely unaffected. The results have implications for next-generation vaccines and antibody therapies.

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