Study: Impact of clade-specific mutations on structural fidelity of SARS-CoV-2 proteins.
Posted on 10/27/2020 9:40:50 AM PDT by SeekAndFind
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, China, in late December 2019. Due to SARS-CoV-2's high infectivity, it spread rapidly across the world. In less than three months, the World Health Organization (WHO) declared the outbreak as the COVID-19 pandemic.
To date, over 41 million cases are reported, with over 1.1 million deaths. Genomic structures and phylogenomic studies reveal that SARS-CoV-2 belongs to genera beta coronavirus (includes SARS-CoV and MERS-CoV (Middle East respiratory syndrome-related coronavirus). However, there are important differences in the genotypic and phenotypic levels that influence their pathogenesis.
While there are variations in severity and lethality of coronaviruses, the infectivity of SARS-CoV-2 is higher than SARS-CoV or MERS-CoV, even though the fatality rate is higher in the latter infections. It is essential to understand the molecular mechanism of SARS-CoV-2 infection to devise therapeutic strategies. In this context, resistant mutations need to be explored to improve any strategy adopted to arrest the infection progression or transmission.
However, there is little focus on mapping the mutations on the important protein components of SARS-CoV-2. Souradip Basu et al. recently published a study exploring clade-specific mutations and their impact on SARS-CoV-2 proteins.
In their bioRxiv* preprint paper, the researchers focus on mapping the clade-specific mutations' effects on the protein structures' conformation and stability. They identified the mutations in the set of seven proteins - orf8, nsp2, nsp4, nsp6, nucleocapsid protein (N), and Spike protein (S).
The SARS-CoV-2 contains a single-stranded positive-sense RNA encapsulated in a nucleoprotein matrix. The RNA genome of SARS-CoV-2 consists of approximately 29,800 nucleotides, encoding for 29 known proteins. Four proteins make up the viral structure.
With the help of a list with prevalent mutations and the NCBI Genome Browser, the researchers created a list of clade-specific mutations in the major pathogenesis proteins of SARS-CoV-2 and their protein sequences. They created two data sets: 1) wild type protein sequences - which were directly the ones from the Wuhan strain, and 2) Mutant Data Set - which consisted of the protein sequences carrying the mutations in them.
Researchers analyzed the physicochemical properties of the proteins. They discuss the secondary structure, accessible surface area, and intrinsic disorder of the protein post mutation in detail. All mutations involved structural changes in the protein, mostly abolishing specific structures such as helices and beta sheets in the proteins.
In this study, the ORF3a protein exhibits decreased disorderedness in its mutant form. This indicates a change in the structural conformation and rigidity of the protein. Also, a maximum change in accessible surface area is observed in S protein. Since the intrinsic disorder was observed to decrease significantly in ORF3a, the role of S protein's functional interaction along with ORF3a is also affected.
The researchers also predict the epitopes in the viral proteins. Epitopes elicit immune responses in the host. These may serve as potent vaccine candidates. Post mutation, they observe a suggestive change in binding efficiencies. This study predicts the possible drug binding sites, along with the druggability of these proteins. The conformational epitopes of B cell, T cell, MHC -I, and MHC –II alleles were also identified.
The authors note that any mutation leads to the structural and functional change in the protein - impairing protein stability.
Using a binary scoring scheme, the authors identify L84S mutation in ORF8 as the most disruptive of the virus's mutations.
Most of us in this pandemic are asymptomatic carriers. With no advanced and assured way of identifying the asymptomatic carriers, there is a high possibility of the successful escape of mutations in the virus's genome. It is imperative to study these mutations and understand its possible impact on infection and response to vaccines and therapeutic agents. This study analyses the effect of prevalent mutations in the SARS-CoV-2 proteins that are primarily related to pathogenesis in humans. The researchers discuss the effects of those mutations on the structural stability of the proteins.
On a positive note, the authors observe 'that the virus is under the influence of an evolutionary phenomenon similar to Muller's ratchet where the continuous accumulation of these mutations makes the virus less virulent, which may also explain the reduction in fatality rates worldwide.'
bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
Evolution dictates viruses evolve up in virulence and down in lethality. A virus measures fitness by the ability to spread and not kill its host too soon, or ideally not kill it at all and spread to everyone and everything. More effective transmission is the evolutionary goal. If this thing is not mutating towards more virulence it is fighting the current that is its evolutionary goal. Artificial means may have been used to maximize this things virulence whether it be CRISPR or artificial mutation/selection for virulence. (ie. Breed a dachshund with a great dane and breed their offspring repeatedly and you get a dog that looks like the Iraqi mutts. Artificial selection breeds out.)
Yet another check mark in the column this was lab created.
This is a well written article. So many science articles are horrible. I see the author has a PhD which probably helps.
Re “Researchers analyzed the physicochemical properties of the proteins”
It should be: “analyzed the _theoretical_ physicochemical properties of the proteins.” It’s all computational. Modeling. Simulation. Good stuff but no physical chemistry or biophysics were done.
As for the premise, I think that there’s no real evidence any of the slight mutations observed have caused the virus to be attenuated in its disease causing potential. Yet that has not been ruled out.
Theoretically a zoonotic disease would have the properties of beginning deadly but changing to a faster spreading but less deadly strain. But there’s really no precedent to know.
Virus mutations can make a virus more or less virulent. But there are several factors to consider. Too much of an increase in virulence and the virus burns itself out by killing its hosts too fast. A significant decrease in virulence turns it into a kitten from a lion. However, the kitten might not resemble the original strain enough to provide protection - we see this with many diseases that have morphed into more or less virulent strains, and even the common cold that mutates often enough that a. there is no “common” cold, really, and b. immunity is unobtainable at our current level of technology.
The original strain, if it finds a sweet-spot like CCP-19 (was apparently engineered for), is not just going to go away. Unless you can contain it, eradicate it, including any reservoirs, it will come back again and again like many strains of various diseases do. The original strain might actually serve as an inoculant against the truly virulent mutations that will kill lots of people really fast. Or it might not. But, again, it isn’t going to go away just because we found a different flavor.
Pinning your hopes on a milder strain is kind of like wandering through traffic and hoping you get hit by a motorcycle instead of a bus. Nothing stopping that bus from running you over, anyway, after the motorcycle softens you up, first.
My understanding is “virulence” is the spreading ability not the pathogenicity. Am I wrong or is the wrong word being used in the article?
This is further data that supports Dr. Li-Meng Yan’s analysis that the virus was manipulated genetically to limit its mortality rate so that it would not be seen by the world as a restricted bioweapon under the Geneva and other international conventions.
It is instead an “unrestricted” bioweapon. Its damage is in creating economic and cultural chaos in the infected enemy population but does not kill their consumers. The idea is to weaken the enemy so they become more dependent on the stronger surviving nation, in this case China.
The CCP 1949-2049 plan is a little ahead of schedule. Now if they can get their candidate Joe Biden elected they will be off to the races. Better brush up on your Mandarin.
Virulence is generally applied to lethality.
“My understanding is “virulence” is the spreading ability not the pathogenicity. Am I wrong or is the wrong word being used in the article?”
Good question and good point. I tend to agree with you but I think it is used interchangeably with pathogenicity, but probably is technically incorrect.
That’s why I said “attenuated disease causing potential” rather than virulence. I think pathogenicity works, less pathogenic as opposed to less virulent.
I don't have enough evidence to believe any of this one way or the other, nor who would benefit the most. Was this retaliation? Was this a warning shot? Is this the start of another Great Reset planned after the 2009-2010 Swine Flu scamdemic by Rockefeller, Rothschild and Gates, et.al. - warning shots by Fauci in 2017 at a CFR meeting to "intimidate" Trump - GAtes' Event 201 in NYC held the same time as the International Military GAmes in Wuhan last fall. So much to contemplate.
On the other hand, despite all the machinations Dr. Li-Meng Yan goes through describing the SARS/Coronavirus19, the CDC stated this in its July report on the PCR Performance Analysis on p.39: The analytical sensitivity of the rRT-PCR assays contained in the CDC 2019 Novel Coronavirus (2019- nCoV) Real-Time RT-PCR Diagnostic Panel were determined in Limit of Detection studies. Since no quantified virus isolates of the 2019-nCoV are currently available, assays designed for detection of the 2019-nCoV RNA were tested with characterized stocks of in vitro transcribed full length RNA (N gene; GenBank accession: MN908947.2) of known titer (RNA copies/µL) spiked into a diluent consisting of a suspension of human A549 cells and viral transport medium (VTM) to mimic clinical specimen. Samples were extracted using the QIAGEN EZ1 Advanced XL instrument and EZ1 DSP Virus Kit (Cat# 62724) and manually with the QIAGEN DSP Viral RNA Mini Kit (Cat# 61904). Real-Time RT-PCR assays were performed using the ThemoFisher Scientific TaqPath™ 1-Step RT-qPCR Master Mix, CG (Cat# A15299) on the Applied Biosystems™ 7500 Fast Dx Real-Time PCR Instrument according to the CDC 2019-nCoV RealTime RT-PCR Diagnostic Panel instructions for use. https://www.fda.gov/media/134922/download
TPTB haven't had to prove a thing - The PCR test does not diagnose anything, especially something that hasn't even been identified. Fear of Covid19 is sufficient to end our Freedom? That's insane. But we are in the midst of a very effective Divide and Conquer campaign. Pick your favorite Slave Master!
If silver killed everything there would me no need for modern medicine. I know you will never stop dispensing inaccurate medical knowledge
So I guess the only thing left is to call out your Bs each time you publish it
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