Impact of B.1.617 and RBD SARS-CoV-2 Variants on Vaccine Efficacy: An In-silico Approach

Abstract The existing panels of COVID-19 vaccines are based on the spike protein of earlier SARS-CoV-2 strain that emerged in Wuhan, China. However, the evolving nature of SARS-CoV-2 has resulted in emergence of new variants, thereby, posing a greater challenge in the management of the disease. India faced a deadlier second wave of infections very recently and genomic surveillance revealed that B.1.617 variant and its sub lineages are responsible for majority of the cases. These are highly infectious and possibly more lethal and therefore labelled as variants of concern by WHO. Hence, it’s crucial to determine if the current vaccines available can be effective against these variants. To address this, we performed molecular dynamics (MD) simulation on B.1.617 along with K417G variants and other RBD variants. We studied structural alteration of the spike protein and factors affecting antibody neutralization and immune escape. We found in seven of the 12 variants studied, there was a structural alteration in RBD region further affecting its stability and function. Docking analysis of RBD variants and wild type strain demonstrated increase in binding affinity with ACE2 (angiotensin 2 altered enzymes) receptor in these variants. Molecular interaction with CR3022 antibody revealed that binding affinity was less in comparison to wild type, with B.1.617 showing the least binding affinity. These findings from the extensive simulations provides novel mechanistic insights on the conformational dynamics and improves our understanding of the enhanced properties of these variants in terms of infectivity, transmissibility, neutralization potential, virulence and host-viral replication fitness.

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Molecular Analysis and Genome Sequencing of SARS-Cov-2 during Second Wave 2021 Revealed Variant Diversity in India

Journal of Pure and Applied Microbiology ◽

10.22207/jpam.15.4.07 ◽

2021 ◽

Author(s):

Rupinder Bakshi ◽

Satinder Kaur ◽

Karashdeep Kaur ◽

Ramanpreet Kaur ◽

Jaspreet Kaur Boparai ◽

...

Keyword(s):

Genome Sequencing ◽

Immune Escape ◽

Age Group ◽

Wild Type ◽

Rt Pcr ◽

Dominant Trait ◽

Male Population ◽

Second Wave ◽

Rapid Emergence ◽

Critical Challenge

SARS-CoV-2 variants rapid emergence has posed critical challenge of higher transmission and immune escape causing serious threats to control the pandemic. The present study was carried out in confirmed cases of SARS-CoV-2 patients to elucidate the prevalence of SARS-CoV-2 variant strain. We performed RT-PCR using extracted RNA from the nasopharyngeal swabs of suspected Covid-19 patients. Confirmed positive cases with CT<25 were subjected to whole-genome sequencing to track the prevalence of the virus in the Malwa region of Punjab. The presence of B.1, B.1.1.7, B.1.351, B.1.617.1, B.1.617.2, AY.1 and other unidentified variants of SARS-CoV-2 was found in the studied population. Among all the variants, B.1.1.7 (UK variant) and B.1.617.2 (delta-Indian variant) was found to be the most dominant variant in the population and was found majorly in Patiala followed by Ludhiana, SBS Nagar, Mansa and Sangrur. In addition to this, sequencing results also observed that the dominant trait was more prevalent in male population and age group 21-40 years. The B.1.1.7 and B.1.617.2 variant of SARS-CoV-2 is replacing the wild type (Wuhan Strain) and emerging as the dominant variant in Punjab.

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Bioinformatics analysis of SARS-CoV-2 RBD mutant variants and insights into antibody and ACE2 receptor binding

10.1101/2021.04.03.438113 ◽

2021 ◽

Author(s):

Prashant Ranjan ◽

Neha ◽

Chandra Devi ◽

Parimal Das

Keyword(s):

Binding Affinity ◽

Receptor Binding ◽

Double Mutant ◽

Structural Changes ◽

Protective Efficacy ◽

Spike Protein ◽

Wild Type ◽

Current Vaccine ◽

New Variant ◽

The Impact

Prevailing COVID-19 vaccines are based on the spike protein of earlier SARS-CoV-2 strain that emerged in Wuhan, China. Continuously evolving nature of SARS-CoV-2 resulting emergence of new variant/s raise the risk of immune absconds. Several RBD (receptor-binding domain) variants have been reported to affect the vaccine efficacy considerably. In the present study, we performed in silico structural analysis of spike protein of double mutant (L452R & E484Q), a new variant of SARS-CoV-2 recently reported in India along with K417G variants and earlier reported RBD variants and found structural changes in RBD region after comparing with the wild type. Comparison of the binding affinity of the double mutant and earlier reported RBD variant for ACE2 (angiotensin 2 altered enzymes) receptor and CR3022 antibody with the wild-type strain revealed the lowest binding affinity of the double mutant for CR3022 among all other variants. These findings suggest that the newly emerged double mutant could significantly reduce the impact of the current vaccine which threatens the protective efficacy of current vaccine therapy.

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Predicting the Potential Effect of E484K Mutation on the Binding of 28 Antibodies to the Spike Protein of SARS-CoV-2 by Molecular Dynamics Simulation and Free Energy Calculation

10.26434/chemrxiv.13897091.v1 ◽

2021 ◽

Cited By ~ 1

Author(s):

Leyun Wu ◽

Cheng Peng ◽

Zhijian Xu ◽

weiliang zhu

Keyword(s):

Free Energy ◽

Binding Affinity ◽

Immune Escape ◽

Binding Free Energy ◽

Experimental Studies ◽

Potential Effect ◽

Dynamics Simulation ◽

Spike Protein ◽

Energy Calculation ◽

Potential Impact

Vaccines and antibody therapeutic are needed to fight the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that has spread since 2020. Experimental studies have shown that the E484K variant may escape the neutralization of antibodies. To explore the potential impact of E484K mutation on the antibody binding affinity, we calculated the binding free energy of 28 antibodies to the wild type and K484 mutant of the spike protein of SARS-CoV-2. We found that 71% of the antibodies show lower binding affinity to the E484K mutant, indicating the highly possible immune escape risk of the mutated virus. Further analysis revealed that the other mutations, e.g. F490 and V483, are also likely to cause immune escape.

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Structural Analysis And Molecular Characteristics of SARSCoV-2 Spike Protein Following S494P Point Mutation: Molecular Dynamics Study

10.21203/rs.3.rs-625623/v1 ◽

2021 ◽

Author(s):

Mehr Ali Mahmood Janlou ◽

Hassan sahebjamee ◽

Shademan Shokravi

Keyword(s):

Structural Analysis ◽

Binding Affinity ◽

Receptor Binding ◽

Conformational Changes ◽

Spike Protein ◽

Molecular Characteristics ◽

Wild Type ◽

Natural Mutation ◽

The Stability ◽

Different Strains

Abstract The emergence of some mutations in the SARS-CoV-2 receptor binding domain (RBD) can increase the spread and pathogenicity due to the conformational changes and increase the stability of Spike protein. Due to the formation of different strains of SARS-CoV-2 by mutations, and their catastrophic effect on public health, the study of the effect of mutations by scientists and researchers around the world is inevitable. According to available evidence, the S494P variant is observed in several SARS-CoV-2 strains from Michigan, USA. To investigate how the S494P natural mutation alters receptor binding affinity in RBD, we performed structural analysis of wild-type and mutant spike proteins using some bioinformatics and computational tools. The results show that S494P mutation increases the spike protein stability. Also, applying docking by HADDOCK displayed higher binding affinity to hACE2 for mutant spike than wild type possibly due to the increased β-strand and Turn secondary structures which increases surface accessibly surface area (SASA) and chance of interaction. The analysis of S494P as a critical RBD mutation may provide the continuing surveillance of spike mutations to aid in the development of COVID-19 drugs and vaccines.

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Possible link between higher transmissibility of B.1.617 and B.1.1.7 variants of SARS-CoV-2 and increased structural stability of its spike protein and hACE2 affinity

10.1101/2021.04.29.441933 ◽

2021 ◽

Author(s):

Vipul Kumar ◽

Jasdeep Singh ◽

Seyed E. Hasnain ◽

Durai Sundar

Keyword(s):

Binding Energy ◽

Immune Escape ◽

Spike Protein ◽

Wild Type ◽

Rt Pcr ◽

Dynamic Simulations ◽

Human Antibodies ◽

Global Pandemic ◽

Hydrogen Interaction ◽

The Stability

AbstractThe Severe Acute syndrome corona Virus 2 (SARS-CoV-2) outbreak in December 2019 has caused a global pandemic. The rapid mutation rate in the virus has caused alarming situations worldwide and is being attributed to the false negativity in RT-PCR tests, which also might lead to inefficacy of the available drugs. It has also increased the chances of reinfection and immune escape. We have performed Molecular Dynamic simulations of three different Spike-ACE2 complexes, namely Wildtype (WT), B.1.1.7 variant (N501Y Spike mutant) and B.1.617 variant (L452R, E484Q Spike mutant) and compared their dynamics, binding energy and molecular interactions. Our result shows that mutation has caused the increase in the binding energy between the Spike and hACE2. In the case of B.1.617 variant, the mutations at L452R and E484Q increased the stability and intra-chain interactions in the Spike protein, which may change the interaction ability of human antibodies to this Spike variant. Further, we found that the B.1.1.7 variant had increased hydrogen interaction with LYS353 of hACE2 and more binding affinity in comparison to WT. The current study provides the biophysical basis for understanding the molecular mechanism and rationale behind the increase in the transmissivity and infectivity of the mutants compared to wild-type SARS-CoV-2.

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Impact of the Double Mutants on Spike Protein of SARS-CoV-2 B.1.617 Lineage to the Human ACE2 Receptor Binding: A Structural Insight

Viruses ◽

10.3390/v13112295 ◽

2021 ◽

Vol 13 (11) ◽

pp. 2295

Author(s):

Mohd Imran Khan ◽

Mohammad Hassan Baig ◽

Tanmoy Mondal ◽

Mohammed Alorabi ◽

Tanuj Sharma ◽

...

Keyword(s):

Binding Affinity ◽

Receptor Binding ◽

Immune Escape ◽

Principal Component ◽

Spike Protein ◽

Human Host ◽

Recent Emergence ◽

Novel Variants ◽

Structural Insight ◽

The Impact

The recent emergence of novel SARS-CoV-2 variants has threatened the efforts to contain the COVID-19 pandemic. The emergence of these “variants of concern” has increased viral transmissibility or immune escape and has supplanted the ancestral strains. The novel variants harbored by the B.1.617 lineage (Kappa and Delta) carry mutations within the receptor-binding domain of spike (S) protein (L452R + E484Q and L452R + T478K), the region binding to the host receptor. The double mutations carried by these novel variants are primarily responsible for an upsurge number of COVID-19 cases in India. In this study, we thoroughly investigated the impact of these double mutations on the binding capability to the human host receptor. We performed several structural analyses and found that the studied double mutations increase the binding affinity of the spike protein to the human host receptor (ACE2). Furthermore, our study showed that these double mutants might be a dominant contributor enhancing the receptor-binding affinity of SARS-CoV-2 and consequently making it more stable. We also investigated the impact of these mutations on the binding affinity of two monoclonal antibodies (Abs) (2-15 and LY-CoV555) and found that the presence of the double mutations also hinders its binding with the studied Abs. The principal component analysis, free energy landscape, intermolecular interaction, and other investigations provided a deeper structural insight to better understand the molecular mechanism responsible for increased viral transmissibility of these variants.

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Predicting the Potential Effect of E484K Mutation on the Binding of 28 Antibodies to the Spike Protein of SARS-CoV-2 by Molecular Dynamics Simulation and Free Energy Calculation

10.26434/chemrxiv.13897091 ◽

2021 ◽

Author(s):

Leyun Wu ◽

Cheng Peng ◽

Zhijian Xu ◽

weiliang zhu

Keyword(s):

Free Energy ◽

Binding Affinity ◽

Immune Escape ◽

Binding Free Energy ◽

Experimental Studies ◽

Potential Effect ◽

Dynamics Simulation ◽

Spike Protein ◽

Energy Calculation ◽

Potential Impact

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Mutations in the B.1.1.7 SARS-CoV-2 spike protein reduce receptor-binding affinity and induce a flexible link to the fusion peptide

10.1101/2021.04.06.438584 ◽

2021 ◽

Author(s):

Eileen Socher ◽

Marcus Conrad ◽

Lukas Heger ◽

Friedrich Paulsen ◽

Heinrich Sticht ◽

...

Keyword(s):

Amino Acid ◽

Binding Affinity ◽

Receptor Binding ◽

Fusion Peptide ◽

Cell Surface Receptor ◽

Spike Protein ◽

Single Amino Acid ◽

Wild Type Virus ◽

Wild Type ◽

Linear Interaction

AbstractThe B.1.1.7 variant of the SARS-CoV-2 virus shows enhanced infectiousness over the wild type virus, leading to increasing patient numbers in affected areas. A number of single amino acid exchanges and deletions within the trimeric viral spike protein characterize this new SARS-CoV-2 variant. Crucial for viral entry into the host cell is the interaction of the spike protein with the cell surface receptor angiotensin-converting enzyme 2 (ACE2) as well as integration of the viral fusion peptide into the host membrane. Respective amino acid exchanges within the SARS-CoV-2 variant B.1.1.7 affect inter-monomeric contact sites within the spike protein (A570D and D614G) as well as the ACE2-receptor interface region (N501Y), which comprises the receptor-binding domain (RBD) of the viral spike protein. However, the molecular consequences of mutations within B.1.1.7 on spike protein dynamics and stability, the fusion peptide, and ACE2 binding are largely unknown. Here, molecular dynamics simulations comparing SARS-CoV-2 wild type with the B.1.1.7 variant revealed inter-trimeric contact rearrangements, altering the structural flexibility within the spike protein trimer. In addition to reduced flexibility in the N-terminal domain of the spike protein, we found increased flexibility in direct spatial proximity of the fusion peptide. This increase in flexibility is due to salt bridge rearrangements induced by the D614G mutation in B.1.1.7 found in pre- and post-cleavage state at the S2’ site. Our results also imply a reduced binding affinity for B.1.1.7 with ACE2, as the N501Y mutation restructures the RBD-ACE2 interface, significantly decreasing the linear interaction energy between the RBD and ACE2.Our results demonstrate how mutations found within B.1.1.7 enlarge the flexibility around the fusion peptide and change the RBD-ACE2 interface, which, in combination, might explain the higher infectivity of B.1.1.7. We anticipate our findings to be starting points for in depth biochemical and cell biological analyses of B.1.1.7, but also other highly contagious SARS-CoV-2 variants, as many of them likewise exhibit a combination of the D614G and N501Y mutation.

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Computational analysis of the effect of SARS-CoV-2 variant Omicron Spike protein mutations on dynamics, ACE2 binding and propensity for immune escape

10.1101/2021.12.14.472622 ◽

2021 ◽

Author(s):

Natalia Teruel ◽

Matthew Crown ◽

Matthew Bashton ◽

Rafael Najmanovich

Keyword(s):

Binding Affinity ◽

Immune Escape ◽

Pearson Correlation ◽

Potential Effect ◽

Spike Protein ◽

Vibrational Entropy ◽

Contributing Factors ◽

S Protein ◽

The One ◽

Opposing Effects

The recently reported Omicron (B.1.1.529) SARS-CoV-2 variant has a large number of mutations in the Spike (S) protein compared to previous variants. Here we evaluate the potential effect of Omicron S mutations on S protein dynamics and ACE2 binding as contributing factors to infectivity as well as propensity for immune escape. We define a consensus set of mutations from 77 sequences assigned as Omicron in GISAID as of November 25. We create structural models of the Omicron S protein in the open and closed states, as part of a complex with ACE2 and for each of 77 complexes of S bound to different antibodies with known structures. We have previously utilized Dynamical Signatures (DS) and the Vibrational Entropy Score (VDS) to evaluate the propensity of S variants to favour the open state. Here, we introduce the Binding Influence Score (BIS) to evaluate the influence of mutations on binding affinity based on the net gain or loss of interactions within the protein-protein interface. BIS shows excellent correlation with experimental data (Pearson correlation coefficient of 0.87) on individual mutations in the ACE2 interface for the Alpha, Beta, Gamma, Delta and Omicron variants combined. On the one hand, the DS of Omicron highly favours a more rigid open state and a more flexible closed state with the largest VDS of all variants to date, suggesting a large increase in the chances to interact with ACE2. On the other hand, the BIS shows that apart from N501Y, all other mutations in the interface reduce ACE2 binding affinity. VDS and BIS show opposing effects on the overall effectiveness of Omicron mutations to promote binding to ACE2 and therefore initiate infection. To evaluate the propensity for immune escape we calculated the net change of favourable and unfavourable interactions within each S-antibody interface. The net change of interactions shows a positive score (a net increase of favourable interactions and decrease of unfavourable ones) for 41 out of 77 antibodies, a nil score for 15 and a negative score for 21 antibodies. Therefore, in only 28% of S-antibody complexes (21/77) we predict some level of immune escape due to a weakening of the interactions with Omicron S. Considering that most antibody epitopes and the mutations are within the S-ACE2 interface our results suggest that mutations within the RBD of Omicron may give rise to only partial immune escape, which comes at the expense of reduced ACE2 binding affinity. However, this reduced ACE2 affinity appears to have been offset by increasing the occupancy of the open state of the Spike protein.

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The circulating SARS-CoV-2 spike variant N439K maintains fitness while evading antibody-mediated immunity

10.1101/2020.11.04.355842 ◽

2020 ◽

Cited By ~ 17

Author(s):

Emma C. Thomson ◽

Laura E. Rosen ◽

James G. Shepherd ◽

Roberto Spreafico ◽

Ana da Silva Filipe ◽

...

Keyword(s):

Immune Evasion ◽

Immune Escape ◽

Binding Motif ◽

Wild Type ◽

Molecular Surveillance ◽

Antibody Therapeutics ◽

Sizeable Fraction ◽

Replication Fitness

SARS-CoV-2 can mutate to evade immunity, with consequences for the efficacy of emerging vaccines and antibody therapeutics. Herein we demonstrate that the immunodominant SARS-CoV-2 spike (S) receptor binding motif (RBM) is the most divergent region of S, and provide epidemiological, clinical, and molecular characterization of a prevalent RBM variant, N439K. We demonstrate that N439K S protein has enhanced binding affinity to the hACE2 receptor, and that N439K virus has similar clinical outcomes and in vitro replication fitness as compared to wild- type. We observed that the N439K mutation resulted in immune escape from a panel of neutralizing monoclonal antibodies, including one in clinical trials, as well as from polyclonal sera from a sizeable fraction of persons recovered from infection. Immune evasion mutations that maintain virulence and fitness such as N439K can emerge within SARS-CoV-2 S, highlighting the need for ongoing molecular surveillance to guide development and usage of vaccines and therapeutics.

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