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Molecular characteristics of SARS-CoV-2 mutant receptor binding

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Since the advent of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), multiple substances of concern (VOCs) have occurred. These variant of concern show increased infectivity, antigenicity, and many vaccines are less effective against them. As the government begins to dismantle pandemic safety measures such as blockades, social distances, and mandatory face masks, cases of coronavirus disease 2019 (COVID-19) are on the rise, many of which are caused by mutations. increase.

study: Molecular insight into the receptor binding of the recently emerging SARS-CoV-2 mutant.. Image Credit: Mediantone / Shutterstock

Of particular concern are delta mutants, which show increased infection and can circumvent both vaccine-induced and innate immunity, currently accounting for more than 90% of new cases. In some cases, the virus spread from humans to animals.In a study published in Nature CommunicationsResearchers at the Chinese Academy of Sciences are investigating changes in receptor binding in these mutants, increasing the risks they pose.

Background

Many vaccines and monoclonal antibodies Spike protein Of SARS-CoV-2. It is the key to the pathogenicity of COVID-19. It consists of two subunits. S1 mainly contains a receptor binding domain (RBD) that binds to angiotensin converting enzyme 2 (ACE2) and enables the invasion of viral cells, and S2 is mainly responsible for membrane fusion. Peplomers are trimers, and many of the mutations they carry affect the conformation of this trimer.

The monomers that form it can be in two positions, one above the other. In the wild type, the monomers primarily exhibit an all-down or one-up-to-down conformation. This makes it less likely to provoke an immune response. However, variants usually show more monomers, increasing ACE2 binding and infectivity.

the study

Researchers have identified six SARS-CoV-2 variants, including alpha, beta, and gamma, for binding to human ACE2, and three strains found in mink (mink-Y453F, mink-F486L, mink-501T). I looked it up. They were then compared to wild-type SARS-CoV-2 binding. Mutant and wild-type RBDs were purified and flow cytometry was used to evaluate ACE2 binding. All mutants commonly found in humans showed increased binding to ACE2 compared to wild-type and two mink mutants.

These interactions were further investigated and surface plasmon resonance (SPR) was used to assess the binding affinity of these RBDs. This is a method that stimulates the vibration of electrons at the interface between negative and positive permittivity materials with light, enabling the material to be adsorbed. measurement. Mouse Fc (mFc) tagged ACE2 was immobilized with an anti-mFC antibody in the chip and the mutant was shed. Mink-N501T showed the highest affinity compared to the wild type, with an 8-fold increase in binding capacity. Alpha, beta, gamma, and mink Y453F RBD all showed higher affinity than wild-type, with increased binding capacity of 7, 3, 5, and 4-fold, respectively.

Next, the researchers investigated which mutations in alpha, beta, and gamma contributed to the different affinities. Alpha contains fewer mutations than the other two variants, but because it exhibits higher affinity, some mutations must result in residues that reduce affinity. Researchers generated single and double mutant RBDs and investigated the binding affinity of ACE2. The two mutations, K417N and K417T, showed reduced affinity as well as the double mutation. E484K showed little effect.

To investigate the underlying mechanism of the difference in binding capacity, researchers created crystal structures at various resolutions of the variant RBD bound to ACE2. Each structure is compromised with one copy of the complex molecule within one unit.

They showed that N501 is located in the loop structure of all human mutants and cannot be replaced by Y. Only weak hydrogen bonds are formed between N501 and ACE2. However, the phenyl in the Y501 side chain shows many sites that can interact with ACE2. These results are supported by previous studies that identified the structure of N501. The reason for the lower binding affinity of gamma and beta compared to alpha can be traced back to the mutations in K417N and K417T that disrupt the salt bridge formed by the K417 and ACE2 residues.

Conclusion

Researchers emphasize the importance of research in characterizing ACE2 binding. This should provide further information on the comparison of transduction efficiencies for SARS-CoV-2 mutants. It helps to understand the transmission of the disease and inform public health policy makers, epidemiologists, and those who model the spread and evolution of the disease. This information can help determine how new variants of the disease can prevent many governments from imposing costly new restrictions-changes that could rekindle the early pandemic economic crisis.

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