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

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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Possible Link between Higher Transmissibility of Alpha, Kappa and Delta Variants of SARS-CoV-2 and Increased Structural Stability of Its Spike Protein and hACE2 Affinity

International Journal of Molecular Sciences ◽

10.3390/ijms22179131 ◽

2021 ◽

Vol 22 (17) ◽

pp. 9131 ◽

Cited By ~ 1

Author(s):

Vipul Kumar ◽

Jasdeep Singh ◽

Seyed E. Hasnain ◽

Durai Sundar

Keyword(s):

Binding Energy ◽

Neutralizing Antibodies ◽

Immune Escape ◽

Spike Protein ◽

Rt Pcr ◽

Dynamic Simulations ◽

Global Pandemic ◽

Hydrogen Interaction ◽

Alpha Variant ◽

The Stability

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) outbreak in December 2019 has caused a global pandemic. The rapid mutation rate in the virus has created alarming situations worldwide and is being attributed to the false negativity in RT-PCR tests. It has also increased the chances of reinfection and immune escape. Recently various lineages namely, B.1.1.7 (Alpha), B.1.617.1 (Kappa), B.1.617.2 (Delta) and B.1.617.3 have caused rapid infection around the globe. To understand the biophysical perspective, we have performed molecular dynamic simulations of four different spikes (receptor binding domain)-hACE2 complexes, namely wildtype (WT), Alpha variant (N501Y spike mutant), Kappa (L452R, E484Q) and Delta (L452R, T478K), and compared their dynamics, binding energy and molecular interactions. Our results show that mutation has caused significant increase in the binding energy between the spike and hACE2 in Alpha and Kappa variants. In the case of Kappa and Delta variants, the mutations at L452R, T478K and E484Q increased the stability and intra-chain interactions in the spike protein, which may change the interaction ability of neutralizing antibodies to these spike variants. Further, we found that the Alpha 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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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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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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Homology Modeling and Evaluation of Sars-Cov-2 Spike Protein Mutant

International Journal of Quantitative Structure-Property Relationships ◽

10.4018/ijqspr.2021100103 ◽

2021 ◽

Vol 6 (4) ◽

pp. 38-55

Author(s):

Hima Vyshnavi ◽

Aswin Mohan ◽

Shahanas Naisam ◽

Suvanish Kumar ◽

Nidhin Sreekumar

Keyword(s):

Molecular Dynamics ◽

Molecular Dynamics Simulation ◽

Antiviral Drug ◽

Dynamics Simulation ◽

Spike Protein ◽

Structure Modeling ◽

Ramachandran Plot ◽

Global Pandemic ◽

The Stability

Severe acute respiratory syndrome coronavirus 2 (SARS‐Cov-2), a global pandemic, affected the world, increasing every day. A mutated variant D614G, showing more virulence and transmission, was studied for forecasting the emergence of more virulent and pathogenic viral strains. This study focuses on structure modeling and validation. Characterization of proteins homologous to wild spike protein was done, and homology models of the mutated variant were modeled using these proteins. Validation of models was done using Ramachandran plot and ERRAT plot. Molecular dynamics simulation was used to validate the stability of the models, and binding affinity of these models were estimated by molecular docking with an approved antiviral drug. Docked complexes were studied and the best model was selected. Molecular dynamics simulation was used to estimate the stability of the docked complex. The model of 6VXX, a homologous of wild spike protein, was found to be stable with the interaction of the antiviral drug from this study.

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Structural insights into SARS-CoV-2 spike protein and its natural mutants found in Mexican population

Scientific Reports ◽

10.1038/s41598-021-84053-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Yudibeth Sixto-López ◽

José Correa-Basurto ◽

Martiniano Bello ◽

Bruno Landeros-Rivera ◽

Jose Antonio Garzón-Tiznado ◽

...

Keyword(s):

Clinical Effect ◽

Experimental Studies ◽

Mexican Population ◽

Spike Protein ◽

Structural Behavior ◽

Molecular Dynamic Simulations ◽

Wild Type ◽

Dynamic Simulations ◽

S Protein ◽

Structural Insights

AbstractThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a newly emerged coronavirus responsible for coronavirus disease 2019 (COVID-19); it become a pandemic since March 2020. To date, there have been described three lineages of SARS-CoV-2 circulating worldwide, two of them are found among Mexican population, within these, we observed three mutations of spike (S) protein located at amino acids H49Y, D614G, and T573I. To understand if these mutations could affect the structural behavior of S protein of SARS-CoV-2, as well as the binding with S protein inhibitors (cepharanthine, nelfinavir, and hydroxychloroquine), molecular dynamic simulations and molecular docking were employed. It was found that these punctual mutations affect considerably the structural behavior of the S protein compared to wild type, which also affect the binding of its inhibitors into their respective binding site. Thus, further experimental studies are needed to explore if these affectations have an impact on drug-S protein binding and its possible clinical effect.

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Developing a Paper-Based Antigen Assay to Differentiate Between Coronaviruses and SARS-CoV-2 Spike Variants

10.26434/chemrxiv.13476738.v1 ◽

2020 ◽

Author(s):

Delyan Hristov ◽

Hom Rijal ◽

Jose Gomez-Marquez ◽

Kimberly Hamad

Keyword(s):

Test Line ◽

Human Saliva ◽

Cross Reactivity ◽

Spike Protein ◽

Signal Quality ◽

Binding Pattern ◽

Rt Pcr ◽

Global Pandemic ◽

Antigen Assay ◽

Assay Design

COVID-19 first appeared in December of 2019 in Wuhan, China. Since then it has become a global pandemic. A robust and scalable diagnostics strategy is crucial for containing and monitoring the pandemic. RT-PCR is a known, reliable method for COVID-19 diagnostics which can differentiate between SARS-CoV-2 and other viruses. However, PCR is location dependent, time consuming and relatively expensive. Thus, there is a need for a more flexible method which may be produced in an off-the-shelf format and distributed more widely. Paper-based immunoassays can fulfill this function. Here we present the first steps towards a paper-based test which can differentiate between different between the Spike protein of various coronaviruses, SARS-CoV-1, SARS-CoV-2 and CoV-HKU1 with negligible cross reactivity for HCoV-OC43 and HCoV-229E in a single assay which takes less than 30 minutes. Furthermore, our test can distinguish between fractions of the same Spike protein. This is done by an altered assay design with four test line locations where each antigen builds a unique, identifiable binding pattern. The effect of several factors, such as running media, immunoprobe concentration and antigen interference is considered. We find that running media has a significant effect on the final binding pattern where human saliva provides results while human serum leads to the lowest signal quality. <br>

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

10.21203/rs.3.rs-713062/v1 ◽

2021 ◽

Author(s):

Prashant Ranjan ◽

Neha ◽

Chandra Devi ◽

Garima Jain ◽

Chandana Basu Mallick ◽

...

Keyword(s):

Binding Affinity ◽

Immune Escape ◽

Conformational Dynamics ◽

Structural Alteration ◽

Spike Protein ◽

Wild Type ◽

Factors Affecting ◽

And Function ◽

Replication Fitness ◽

Second Wave

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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