Scanning the RBD-ACE2 molecular interactions in Omicron variant

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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Strong evolutionary convergence of receptor-binding protein spike between COVID-19 and SARS-related coronaviruses

10.1101/2020.03.04.975995 ◽

2020 ◽

Cited By ~ 6

Author(s):

Yonghua Wu

Keyword(s):

Receptor Binding ◽

Molecular Basis ◽

Acid Sites ◽

Spike Protein ◽

Receptor Binding Domain ◽

Angiotensin Converting Enzyme 2 ◽

Partner Protein ◽

Evolutionary Convergence ◽

Genome Level ◽

Phenotypic Convergence

AbstractCoronavirus Disease 2019 (COVID-19) and severe acute respiratory syndrome (SARS)-related coronaviruses (e.g., 2019-nCoV and SARS-CoV) are phylogenetically distantly related, but both are capable of infecting human hosts via the same receptor, angiotensin-converting enzyme 2, and cause similar clinical and pathological features, suggesting their phenotypic convergence. Yet, the molecular basis that underlies their phenotypic convergence remains unknown. Here, we used a recently developed molecular phyloecological approach to examine the molecular basis leading to their phenotypic convergence. Our genome-level analyses show that the spike protein, which is responsible for receptor binding, has undergone significant Darwinian selection along the branches related to 2019-nCoV and SARS-CoV. Further examination shows an unusually high proportion of evolutionary convergent amino acid sites in the receptor binding domain (RBD) of the spike protein between COVID-19 and SARS-related CoV clades, leading to the phylogenetic uniting of their RBD protein sequences. In addition to the spike protein, we also find the evolutionary convergence of its partner protein, ORF3a, suggesting their possible co-evolutionary convergence. Our results demonstrate a strong adaptive evolutionary convergence between COVID-19 and SARS-related CoV, possibly facilitating their adaptation to similar or identical receptors. Finally, it should be noted that many observed bat SARS-like CoVs that have an evolutionary convergent RBD sequence with 2019-nCoV and SARS-CoV may be pre-adapted to human host receptor ACE2, and hence would be potential new coronavirus sources to infect humans in the future.

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S19W, T27W, and N330Y mutations in ACE2 enhance SARS-CoV-2 S-RBD binding toward both wild-type and antibody-resistant viruses and its molecular basis

Signal Transduction and Targeted Therapy ◽

10.1038/s41392-021-00756-4 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Fei Ye ◽

Xi Lin ◽

Zimin Chen ◽

Fanli Yang ◽

Sheng Lin ◽

...

Keyword(s):

Molecular Basis ◽

Structural Data ◽

Van Der Waals Interactions ◽

Side Chains ◽

Receptor Binding Domain ◽

Converting Enzyme ◽

Wild Type ◽

Angiotensin Converting Enzyme 2 ◽

Domain Protein ◽

Entry Inhibition

AbstractSARS-CoV-2 recognizes, via its spike receptor-binding domain (S-RBD), human angiotensin-converting enzyme 2 (ACE2) to initiate infection. Ecto-domain protein of ACE2 can therefore function as a decoy. Here we show that mutations of S19W, T27W, and N330Y in ACE2 could individually enhance SARS-CoV-2 S-RBD binding. Y330 could be synergistically combined with either W19 or W27, whereas W19 and W27 are mutually unbeneficial. The structures of SARS-CoV-2 S-RBD bound to the ACE2 mutants reveal that the enhanced binding is mainly contributed by the van der Waals interactions mediated by the aromatic side-chains from W19, W27, and Y330. While Y330 and W19/W27 are distantly located and devoid of any steric interference, W19 and W27 are shown to orient their side-chains toward each other and to cause steric conflicts, explaining their incompatibility. Finally, using pseudotyped SARS-CoV-2 viruses, we demonstrate that these residue substitutions are associated with dramatically improved entry-inhibition efficacy toward both wild-type and antibody-resistant viruses. Taken together, our biochemical and structural data have delineated the basis for the elevated S-RBD binding associated with S19W, T27W, and N330Y mutations in ACE2, paving the way for potential application of these mutants in clinical treatment of COVID-19.

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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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Evidence for adaptive evolution in the receptor-binding domain of seasonal coronaviruses OC43 and 229e

eLife ◽

10.7554/elife.64509 ◽

2021 ◽

Vol 10 ◽

Cited By ~ 4

Author(s):

Kathryn E Kistler ◽

Trevor Bedford

Keyword(s):

Adaptive Evolution ◽

Immune Evasion ◽

Human Population ◽

Seasonal Influenza ◽

Respiratory Infections ◽

Antigenic Drift ◽

Spike Protein ◽

Immune Memory ◽

Receptor Binding Domain ◽

Genetic Changes

Seasonal coronaviruses (OC43, 229E, NL63, and HKU1) are endemic to the human population, regularly infecting and reinfecting humans while typically causing asymptomatic to mild respiratory infections. It is not known to what extent reinfection by these viruses is due to waning immune memory or antigenic drift of the viruses. Here we address the influence of antigenic drift on immune evasion of seasonal coronaviruses. We provide evidence that at least two of these viruses, OC43 and 229E, are undergoing adaptive evolution in regions of the viral spike protein that are exposed to human humoral immunity. This suggests that reinfection may be due, in part, to positively selected genetic changes in these viruses that enable them to escape recognition by the immune system. It is possible that, as with seasonal influenza, these adaptive changes in antigenic regions of the virus would necessitate continual reformulation of a vaccine made against them.

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Mechanistic Insights into the Effects of Key Mutations on SARS-CoV-2 RBD-ACE2 Binding

10.1101/2021.09.20.461041 ◽

2021 ◽

Author(s):

Abhishek Aggarwal ◽

Supriyo Naskar ◽

Nikhil Maroli ◽

Biswajit Gorai ◽

Narendra M Dixit ◽

...

Keyword(s):

Structural Changes ◽

Underlying Mechanism ◽

Free Energy Calculations ◽

Target Cells ◽

Original Strain ◽

Binding Affinities ◽

Receptor Binding Domain ◽

Wild Type ◽

Dynamics Simulations ◽

Insight Into

Some recent SARS-CoV-2 variants appear to have increased transmissibility than the original strain. An underlying mechanism could be the improved ability of the variants to bind receptors on target cells and infect them. In this study, we provide atomic-level insight into the binding of the receptor binding domain (RBD) of the wild-type SARS-CoV-2 spike protein and its single (N501Y), double (E484Q, L452R) and triple (N501Y, E484Q, L452R) mutated variants to the human ACE2 receptor. Using extensive all-atom molecular dynamics simulations and advanced free energy calculations, we estimate the associated binding affinities and binding hotspots. We observe significant secondary structural changes in the RBD of the mutants, which lead to different binding affinities. We find higher binding affinities of the double (E484Q, L452R) and triple (N501Y, E484Q, L452R) mutated variants than the wild type and the N501Y variant, which could contribute to the higher transmissibility of recent variants containing these mutations.

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SARS-CoV-2 variants resist antibody neutralization and broaden host ACE2 usage

10.1101/2021.03.09.434497 ◽

2021 ◽

Author(s):

Ruoke Wang ◽

Qi Zhang ◽

Jiwan Ge ◽

Wenlin Ren ◽

Rui Zhang ◽

...

Keyword(s):

South Africa ◽

Monoclonal Antibodies ◽

Molecular Basis ◽

Spike Protein ◽

Receptor Binding Domain ◽

Antibody Neutralization ◽

Vaccine Protection ◽

Antigenic Sites ◽

Global Pandemic ◽

Crystal Structural

AbstractNew SARS-CoV-2 variants continue to emerge from the current global pandemic, some of which can replicate faster and with greater transmissibility and pathogenicity. In particular, UK501Y.V1 identified in UK, SA501Y.V2 in South Africa, and BR501Y.V3 in Brazil are raising serious concerns as they spread quickly and contain spike protein mutations that may facilitate escape from current antibody therapies and vaccine protection. Here, we constructed a panel of 28 SARS-CoV-2 pseudoviruses bearing single or combined mutations found in the spike protein of these three variants, as well as additional nine mutations that within or close by the major antigenic sites in the spike protein identified in the GISAID database. These pseudoviruses were tested against a panel of monoclonal antibodies (mAbs), including some approved for emergency use to treat SARS-CoV-2 infection, and convalescent patient plasma collected early in the pandemic. SA501Y.V2 pseudovirus was the most resistant, in magnitude and breadth, against mAbs and convalescent plasma, followed by BR501Y.V3, and then UK501Y.V1. This resistance hierarchy corresponds with Y144del and 242-244del mutations in the N-terminal domain as well as K417N/T, E484K and N501Y mutations in the receptor binding domain (RBD). Crystal structural analysis of RBD carrying triple K417N-E484K-N501Y mutations found in SA501Y.V2 bound with mAb P2C-1F11 revealed a molecular basis for antibody neutralization and escape. SA501Y.V2 and BR501Y.V3 also acquired substantial ability to use mouse and mink ACE2 for entry. Taken together, our results clearly demonstrate major antigenic shifts and potentially broadening the host range of SA501Y.V2 and BR501Y.V3, which pose serious challenges to our current antibody therapies and vaccine protection.

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Dynamics of the ACE2 - SARS-CoV/SARS-CoV-2 spike protein interface reveal unique mechanisms

10.1101/2020.06.10.143990 ◽

2020 ◽

Author(s):

Amanat Ali ◽

Ranjit Vijayan

Keyword(s):

Salt Bridge ◽

Spike Protein ◽

Health Concern ◽

Treatment Modalities ◽

Receptor Binding Domain ◽

Public Health Concern ◽

Angiotensin Converting Enzyme 2 ◽

Dynamics Simulations ◽

And Function ◽

Host Target

AbstractThe coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a major public health concern. A handful of static structures now provide molecular insights into how SARS-CoV-2 and SARS-CoV interact with its host target, which is the angiotensin converting enzyme 2 (ACE2). Molecular recognition, binding and function are dynamic processes. To evaluate this, multiple all atom molecular dynamics simulations of at least 500 ns each were performed to better understand the structural stability and interfacial interactions between the receptor binding domain of the spike protein of SARS-CoV-2 and SARS-CoV bound to ACE2. Several contacts were observed to form, break and reform in the interface during the simulations. Our results indicate that SARS-CoV and SARS-CoV-2 utilizes unique strategies to achieve stable binding to ACE2. Several differences were observed between the residues of SARS-CoV-2 and SARS-CoV that consistently interacted with ACE2. Notably, a stable salt bridge between Lys417 of SARS-CoV-2 spike protein and Asp30 of ACE2 as well as three stable hydrogen bonds between Tyr449, Gln493, and Gln498 of SARS-CoV-2 and Asp38, Glu35, and Lys353 of ACE2 were observed, which were absent in the SARS-CoV-ACE2 interface. Some previously reported residues, which were suggested to enhance the binding affinity of SARS-CoV-2, were not observed to form stable interactions in these simulations. Stable binding to the host receptor is crucial for virus entry. Therefore, special consideration should be given to these stable interactions while designing potential drugs and treatment modalities to target or disrupt this interface.

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

10.1101/2021.02.17.431625 ◽

2021 ◽

Author(s):

Saman Fatihi ◽

Surabhi Rathore ◽

Ankit Pathak ◽

Deepanshi Gahlot ◽

Mitali Mukerji ◽

...

Keyword(s):

Genomic Data ◽

Structural Features ◽

Antigenic Drift ◽

Spike Protein ◽

Wild Type ◽

Genome Sequences ◽

Host Interactions ◽

Rigorous Framework ◽

Dynamics Simulations ◽

Viral Host Interactions

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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SARS-CoV-2 Spike receptor-binding domain with a G485R mutation in complex with human ACE2

10.1101/2021.03.16.434488 ◽

2021 ◽

Author(s):

Claire M. Weekley ◽

Damian F. J. Purcell ◽

Michael W. Parker

Keyword(s):

Receptor Binding ◽

Point Mutations ◽

Direct Interaction ◽

Binding Domain ◽

Spike Protein ◽

Genomic Sequencing ◽

Binding Motif ◽

Receptor Binding Domain ◽

Structural Characterisation ◽

Human Receptor

AbstractSince SARS-CoV-2 emerged in 2019, genomic sequencing has identified mutations in the viral RNA including in the receptor-binding domain of the Spike protein. Structural characterisation of the Spike carrying point mutations aids in our understanding of how these mutations impact binding of the protein to its human receptor, ACE2, and to therapeutic antibodies. The Spike G485R mutation has been observed in multiple isolates of the virus and mutation of the adjacent residue E484 to lysine is known to contribute to antigenic escape. Here, we have crystallised the SARS-CoV-2 Spike receptor-binding domain with a G485R mutation in complex with human ACE2. The crystal structure shows that while the G485 residue does not have a direct interaction with ACE2, its mutation to arginine affects the structure of the loop made by residues 480-488 in the receptor-binding motif, disrupting the interactions of neighbouring residues with ACE2 and with potential implications for antigenic escape from vaccines, antibodies and other biologics directed against SARS-CoV-2 Spike.

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Molecular basis for SARS-CoV-2 spike affinity for human ACE2 receptor

10.1101/2020.09.10.291757 ◽

2020 ◽

Author(s):

Julián M. Delgado ◽

Nalvi Duro ◽

David M. Rogers ◽

Alexandre Tkatchenko ◽

Sagar A. Pandit ◽

...

Keyword(s):

Molecular Dynamics ◽

Molecular Basis ◽

Free Energy Calculations ◽

Spike Protein ◽

Salt Bridges ◽

Recognition Mechanism ◽

X Ray ◽

Receptor Recognition ◽

Structural Fluctuations ◽

Dynamics Simulations

AbstractSevere acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused substantially more infections, deaths, and economic disruptions than the 2002-2003 SARS-CoV. The key to understanding SARS-CoV-2’s higher infectivity may lie in its host receptor recognition mechanism. This is because experiments show that the human ACE2 protein, which serves as the primary receptor for both CoVs, binds to CoV-2’s spike protein 5-20 fold stronger than SARS-CoV’s spike protein. The molecular basis for this difference in binding affinity, however, remains unexplained and, in fact, a comparison of X-ray structures leads to an opposite proposition. To gain insight, we use all-atom molecular dynamics simulations. Free energy calculations indicate that CoV-2’s higher affinity is due primarily to differences in specific spike residues that are local to the spike-ACE2 interface, although there are allosteric effects in binding. Comparative analysis of equilibrium simulations reveals that while both CoV and CoV-2 spike-ACE2 complexes have similar interfacial topologies, CoV-2’s spike protein engages in greater numbers, combinatorics and probabilities of hydrogen bonds and salt bridges with ACE2. We attribute CoV-2’s higher affinity to these differences in polar contacts, and these findings also highlight the importance of thermal structural fluctuations in spike-ACE2 complexation. We anticipate that these findings will also inform the design of spike-ACE2 peptide blockers that, like in the cases of HIV and Influenza, can serve as antivirals.

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