scholarly journals The High Transmission of SARS-CoV-2 Omicron (B.1.1.529) Variant is Not Only Due to Its hACE2 binding: A Free Energy of Perturbation Study

2021 ◽  
Author(s):  
Filip Fratev
Keyword(s):  
South Africa ◽  
Free Energy ◽  
Molecular Level ◽  
Binding Capacity ◽  
Spike Protein ◽  
Structural Basis ◽  
New Variant ◽  
Alpha Variant ◽  
Special Circumstances ◽  
Interaction Surface

AbstractThe mutations in the spike protein of SARS-CoV-2 Omicron variant (B.1.1.529 lineage) gave rise to questions, but the data on the mechanism of action at the molecular level is limited. In this study, we present the Free energy of perturbation (FEP) data about the RBD-hACE2 binding of this new variant.We identified two groups of mutations located close to the most contributing substitutions Q498R and Q493R, which altered significantly the RBD-hACE2 interactions. The Q498R, Y505H and G496S mutations, in addition to N501Y, highly increased the binding to hACE2. They enhanced the binding by 98, 14 and 13 folds, respectively, which transforms the S1-RBD to a picomolar binder. However, in contrast to the case in mice the Q493R/K mutations, in a combination with K417N and T478K, dramatically reduced the S1 RBD binding by over 100 folds. The N440K, G446S and T478K substitutions had lesser contribution. Thus, the total effect of these nine mutations located on the interaction surface of RBD-hACE2 turns out to be similar to that observed in the Alpha variant. In a special circumstances it could be further altered by the E484A and S477N mutations and even lower binding capacity is likely to be detected. Finally, we provide a structural basis of the observed changes in the interactions.These data may explain only partially the observed in South Africa extremely high Omicron spread and is in support to the hypothesis for multiple mechanisms of actions involved in the transmission.Graphical abstract

scholarly journals The N501Y and K417N mutations in the spike protein of SARS-CoV-2 alter the interactions with both hACE2 and human derived antibody: A Free energy of perturbation study

2020 ◽  
Author(s):  
Filip Fratev
Keyword(s):  
South Africa ◽  
Immune Response ◽  
Free Energy ◽  
Molecular Level ◽  
Spike Protein ◽  
Free Energy Perturbation ◽  
Receptor Binding Domain ◽  
Human Immune Response ◽  
Human Immune ◽  
Energy Perturbation

AbstractThe N501Y and K417N mutations in spike protein of SARS-CoV-2 and their combination arise questions but the data about their mechanism of action at molecular level is limited. Here, we present Free energy perturbation (FEP) calculations for the interactions of the spike S1 receptor binding domain (RBD) with both the ACE2 receptor and an antibody derived from COVID-19 patients. Our results shown that the S1 RBD-ACE2 interactions were significantly increased whereas those with the STE90-C11 antibody dramatically decreased; about over 100 times. The K417N mutation had much more pronounced effect and in a combination with N501Y fully abolished the antibody effect. This may explain the observed in UK and South Africa more spread of the virus but also raise an important question about the possible human immune response and the success of already available vaccines.

scholarly journals Structural analysis of the Spike of the Omicron SARS-COV-2 variant by Cryo-EM and implications for immune evasion

2021 ◽  
Author(s):  
Dongchun Ni ◽  
Kelvin Lau ◽  
Priscilla Turelli ◽  
Charlene Raclot ◽  
Bertrand Beckert ◽  
...  
Keyword(s):  
South Africa ◽  
United Kingdom ◽  
Structural Analysis ◽  
High Resolution ◽  
Immune Evasion ◽  
Spike Protein ◽  
Spike Glycoprotein ◽  
The United Kingdom ◽  
New Variant ◽  
Structural Insights

The Omicron (B.1.1.529) SARS-COV-2 was reported on November 24, 2021 and declared a variant of concern a couple of days later. With its constellation of mutations acquired by this variant on its Spike glycoprotein and the speed at which this new variant has replaced the previously dominant variant Delta in South Africa and the United Kingdom, it is crucial to have atomic structural insights to reveal the mechanism of its rapid proliferation. Here we present a high-resolution cryo-EM structure of the Spike protein of the Omicron variant.

scholarly journals Increased neutralization of SARS-CoV-2 Delta variant by nanobody (Nb22) and the structural basis

2021 ◽  
Author(s):  
Xilin Wu ◽  
Yaxing Wang ◽  
Lin Cheng ◽  
Linjing Zhu ◽  
Sen Ma ◽  
...  
Keyword(s):  
Hydrogen Bond ◽  
Therapeutic Agent ◽  
Spike Protein ◽  
Structural Basis ◽  
Receptor Binding Domain ◽  
Ic50 Value ◽  
Additional Hydrogen Bond ◽  
Crystal Structural ◽  
Alpha Variant ◽  
Additional Hydrogen

Delta variant, also known as B.1.617.2, has become a predominant circulating variant in many countries since it first emerged in India in December 2020. Delta variant is less sensitive to serum neutralization from COVID-19 convalescent individuals or vaccine recipients, relative to Alpha strains. It was also resistant to neutralization by some anti-receptor binding domain (RBD) and anti-N-terminal domain (NTD) antibodies in clinics. Previously, we reported the discovery of nanobodies isolated from an alpaca immunized with spike protein, exhibiting ultrahigh potency against SARS-CoV-2 and its mutated variants, where a novel inhalable bispecific Nb15 protected SARS-CoV-2 infection in hACE2 mice. Here, we found that Nb22-Fc, among our previously reported nanobodies, exhibited 8.4-fold increased neutralization potency against Delta variant with an IC50 value of 0.41 ng/ml (5.13 pM) relative to Alpha variant. Furthermore, our crystal structural analysis reveals that the binding of Nb22 on SARS-CoV-2 RBD effectively blocks the binding of RBD to ACE2 during virus infection. Furthermore, the L452R mutation in RBD of Delta variant forms an additional hydrogen bond with the hydroxy group of T30 of Nb22, leading to the increased neutralization potency of Nb22 against Delta variant. Thus, Nb22 is a potential therapeutic agent against SARS-CoV-2, especially the highly contagious Delta variant.

scholarly journals E156/G and Arg158, Phe-157/del mutation in NTD of spike protein in B.1.167.2 lineage of SARS-CoV-2 leads to immune evasion through antibody escape

2021 ◽  
Author(s):  
Armi Chaudhari ◽  
Dinesh Kumar ◽  
Dr. Madhvi Joshi ◽  
Amrutlal Patel ◽  
Prof. Chaitanya joshi
Keyword(s):  
Immune Escape ◽  
Spike Protein ◽  
Structural Basis ◽  
Virus Particles ◽  
Fitness Advantage ◽  
Pathogenic Virus ◽  
New Variant ◽  
Significant Difference ◽  
Dynamics Simulations ◽  
Immune Escape Mechanisms

New emerging variants of SARS-CoV-2 remains a persistent threat with better immune escape mechanisms and higher transmissibility across the globe. B.1.617.2 (Delta) variant first emerged from Maharashtra, India in December, 2020. This variant is classified to be a major cause and concern of the recent peak of COVID-19 in India. Cellular entry of coronaviruses largely depends on binding of the viral spike (S) proteins to host receptors and priming by host cell proteases through the contact of the droplets containing pathogenic virus particles. Our research study, explore the genomic and structural basis of this variant through computational analysis, protein modelling and molecular dynamics simulations approach and identifies the mechanism through which it is probably more pathogenically evolved with higher transmissibility as compared to the wild-type. These findings reveal the significant difference in rigidity and reducing the flexibility within N-terminal domain (NTD) of the spike protein, hence prevailing case of antibody escape. The results of the present study demonstrate the fitness advantage to the new variant which further need to be critically examined though supportive experimental biology that might help devising better therapeutics and containment of SARS-CoV-2.

scholarly journals Improved binding affinity of the Omicron's spike protein with hACE2 receptor is the key factor behind its increased virulence

2021 ◽  
Author(s):  
Rajender Kumar ◽  
Murugan Natarajan Arul ◽  
Vaibhav Srivastava
Keyword(s):  
Free Energy ◽  
Hydrogen Bonding ◽  
Binding Affinity ◽  
Electrostatic Interactions ◽  
Binding Free Energy ◽  
Free Energy Calculations ◽  
Spike Protein ◽  
Strong Interactions ◽  
Salt Bridges ◽  
New Variant

The new variant of SARS-CoV-2, Omicron, has been quickly spreading in many countries worldwide. Compared to the original virus, Omicron is characterized by several mutations in its genomic region, including spike protein's receptor-binding domain (RBD). We have computationally investigated the interaction between RBD of both wild-type and omicron variants with hACE2 receptor using molecular dynamics and MM-GBSA based binding free energy calculations. The mode of the interaction between Omicron's RBD to the human ACE2 (hACE2) receptor is similar to the original SARS-CoV-2 RBD except for a few key differences. The bind-ing free energy difference shows that the spike protein of Omicron has increased binding affinity for the hACE-2 receptor. The mutated residues in the RBD showed strong interactions with a few amino acid residues of the hACE2. More specifically, strong electrostatic interactions (salt bridges) and hydrogen bonding were observed between R493 and R498 residues of the Omicron RBD with D30/E35 and D38 residues of the hACE2, respectively. Other mutated amino acids in the Omicron RBD, e.g. S496 and H505, also exhibited hydrogen bonding with the hACE2 receptor. The pi-stacking interaction was also observed between tyrosine residues (RBD-Tyr501: hACE2-Tyr41) in the complex, which contributes majorly to binding free energies suggesting this as one of the key interactions stabilizing the complex formation. The structural insights of RBD:hACE2 complex, their binding mode information and residue wise contributions to binding free energy provide insight on the increased transmissibility of Omicron and pave the way to design and optimize novel antiviral agents.

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

Viruses ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 633
Author(s):  
Yeong Jun Kim ◽  
Ui Soon Jang ◽  
Sandrine M. Soh ◽  
Joo-Youn Lee ◽  
Hye-Ra Lee
Keyword(s):  
South Africa ◽  
Monoclonal Antibodies ◽  
Cell Fusion ◽  
Receptor Binding ◽  
Neutralizing Antibodies ◽  
Receptor Binding Domain ◽  
Viral Spread ◽  
New Variant ◽  
Global Concern ◽  
The Impact

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.

Structural Basis for the Understanding of Entry Inhibitors Against SARS Viruses

2021 ◽  
Vol 28 ◽  
Author(s):  
Prem Kumar Kushwaha ◽  
Neha Kumari ◽  
Sneha Nayak ◽  
Keshav Kishor ◽  
Ashoke Sharon
Keyword(s):  
Viral Entry ◽  
Molecular Level ◽  
Virus Entry ◽  
Holistic Approach ◽  
Symptomatic Treatment ◽  
Host Cells ◽  
Structural Basis ◽  
Viral Fusion ◽  
Structural Studies ◽  
Entry Inhibitors

: Outbreaks due to Severe Acute Respiratory Syndrome-Corona virus 2 (SARS-CoV-2) initiated in Wuhan city, China, in December 2019 which continued to spread internationally, posing a pandemic threat as declared by WHO and as of March 10, 2021, confirmed cases reached 118 million along with 2.6 million deaths worldwide. In the absence of specific antiviral medication, symptomatic treatment and physical isolation remain the options to control the contagion. The recent clinical trials on antiviral drugs highlighted some promising compounds such as umifenovir (haemagglutinin-mediated fusion inhibitor), remdesivir (RdRp nucleoside inhibitor), and favipiravir (RdRp Inhibitor). WHO launched a multinational clinical trial on several promising analogs as a potential treatment to combat SARS infection. This situation urges a holistic approach to invent safe and specific drugs as a prophylactic and therapeutic cure for SARS-related-viral diseases, including COVID-19. : It is significant to note that researchers worldwide have been doing their best to handle the crisis and have produced an extensive and promising literature body. It opens a scope and allows understanding the viral entry at the molecular level. A structure-based approach can reveal the molecular-level understanding of viral entry interaction. The ligand profiling and non-covalent interactions among participating amino-acid residues are critical information to delineate a structural interpretation. The structural investigation of SARS virus entry into host cells will reveal the possible strategy for designing drugs like entry inhibitors. : The structure-based approach demonstrates details at the 3D molecular level. It shows specificity about SARS-CoV-2 spike interaction, which uses human angiotensin-converting enzyme 2 (ACE2) as a receptor for entry, and the human protease completes the process of viral fusion and infection. : The 3D structural studies reveal the existence of two units, namely S1 and S2. S1 is called a receptor-binding domain (RBD) and responsible for interacting with the host (ACE2), and the S2 unit participates in the fusion of viral and cellular membranes. TMPRSS2 mediates the cleavage at S1/S2 subunit interface in S-protein of SARS CoV-2, leading to viral fusion. Conformational difference associated with S1 binding alters ACE2 interaction and inhibits viral fusion. Overall, the detailed 3D structural studies help understand the 3D structural basis of interaction between viruses with host factors and available scope for the new drug discovery process targeting SARS-related virus entry into the host cell.

Compared with SARS-CoV2 wild type's spike protein, the SARS-CoV2 omicron's receptor binding motif has adopted a more SARS-CoV1 and/or bat/civet-like structure.

2021 ◽  
Author(s):  
Michael O. Glocker ◽  
Kwabena F. M. Opuni ◽  
Hans-Juergen Thiesen
Keyword(s):  
Free Energy ◽  
Receptor Binding ◽  
Free Energy Calculations ◽  
Viral Fitness ◽  
Spike Protein ◽  
Receptor Protein ◽  
Binding Motif ◽  
Energy Calculations ◽  
Selection Processes ◽  
Protein Receptor

Our study focuses on free energy calculations of SARS-Cov2 spike protein receptor binding motives (RBMs) from wild type and variants-of-concern with particular emphasis on currently emerging SARS- CoV2 omicron variants of concern (VOC). Our computational free energy analysis underlines the occurrence of positive selection processes that specify omicron host adaption and bring changes on the molecular level into context with clinically relevant observations. Our free energy calculations studies regarding the interaction of omicron's RBM with human ACE2 shows weaker binding to ACE2 than alpha's, delta's, or wild type's RBM. Thus, less virus is predicted to be generated in time per infected cell. Our mutant analyses predict with focus on omicron variants a reduced spike-protein binding to ACE2--receptor protein possibly enhancing viral fitness / transmissibility and resulting in a delayed induction of danger signals as trade-off. Finally, more virus is produced but less per cell accompanied with delayed Covid-19 immunogenicity and pathogenicity. Regarding the latter, more virus is assumed to be required to initiate inflammatory immune responses.

scholarly journals Extremely potent monoclonal antibodies neutralize Omicron and other SARS-CoV-2 variants

2022 ◽  
Author(s):  
Zhaochun Chen ◽  
Peng Zhang ◽  
Yumiko Matsuoka ◽  
Yaroslav Tsybovsky ◽  
Kamille West ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Neutralizing Antibodies ◽  
Spike Protein ◽  
Structural Basis ◽  
Hamster Model ◽  
Golden Syrian Hamster ◽  
Phage Display Libraries ◽  
Antibody Phage ◽  
Antibody Phage Display ◽  
Early Isolate

The ongoing coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has triggered a devastating global health, social and economic crisis. The RNA nature and broad circulation of this virus facilitate the accumulation of mutations, leading to the continuous emergence of variants of concern with increased transmissibility or pathogenicity1. This poses a major challenge to the effectiveness of current vaccines and therapeutic antibodies1,2. Thus, there is an urgent need for effective therapeutic and preventive measures with a broad spectrum of action, especially against variants with an unparalleled number of mutations such as the recently emerged Omicron variant, which is rapidly spreading across the globe3. Here, we used combinatorial antibody phage-display libraries from convalescent COVID-19 patients to generate monoclonal antibodies against the receptor-binding domain of the SARS-CoV-2 spike protein with ultrapotent neutralizing activity. One such antibody, NE12, neutralizes an early isolate, the WA-1 strain, as well as the Alpha and Delta variants with half-maximal inhibitory concentrations at picomolar level. A second antibody, NA8, has an unusual breadth of neutralization, with picomolar activity against both the Beta and Omicron variants. The prophylactic and therapeutic efficacy of NE12 and NA8 was confirmed in preclinical studies in the golden Syrian hamster model. Analysis by cryo-EM illustrated the structural basis for the neutralization properties of NE12 and NA8. Potent and broadly neutralizing antibodies against conserved regions of the SARS-CoV-2 spike protein may play a key role against future variants of concern that evade immune control.

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