Sun. Oct 17th, 2021

The initial strain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was found in Wuhan, China. Due to the high transmission rates, the virus spread rapidly around the world. Over 4.87 million people have died so far and many countries have been plunged into economic crises due to the harsh restrictions required to prevent further spread of the disease. These included measures for social distance, face masks and in many countries complete lockdowns.

Study: SARS-CoV-2 variants exhibit increased kinetic stability of open spike conformations as an evolutionary strategy.  Image credit: Adao / ShutterstockStudy: SARS-CoV-2 variants exhibit increased kinetic stability of open spike conformations as an evolutionary strategy. Image credit: Adao / Shutterstock

Mass vaccination schemes are beginning to make it possible to remove some of these restrictions, but there are still concerns about dangerous variants of concern (VOCs) that are becoming more widespread. One of the most worrying strains is the Delta variant – currently the most common cause of new infections worldwide. The Delta variant and other strains carrying the D614G mutation have been known to avoid both vaccine-induced and natural immunity. Researchers from Yale University and the University of Texas have collaborated to investigate mutations in some VOCs.

A pre-printed version of the survey is available at bioRxiv* server while the article is undergoing peer review.

Background

Among other mutations, D614G alters the conformation of the highly glycosylated pig protein. The spike protein is the key to SARS-CoV-2 pathogenicity. The receptor binding domain (RBD) of the S1 subunit can bind to angiotensin-converting enzyme 1 (ACE1) and neuropilin 1 to allow viral cell penetration, and the N-terminal domain is essential for membrane fusion.

For this reason, most vaccines target a region of the spike protein, and many studies examine the seroprevalence of anti-SARS-CoV-2 immune response assays looking for antibodies targeted to the spike protein. E484K is another known mutation that can help avoid the immune response, and several other mutations such as L452R, N501Y and P681R have been known to play similar roles.

The study

The spike protein has four different possible conformations based on the orientation of individual protomers — these are “one-RBD-up”, “two-RBD-up”, “all-RBD-up” and “all-RBD-down”. Using the single-molecule Forster Resonance Energy Transfer (smFRET), researchers have studied the ability of viruses to move between these states in real time and the conformations that exist during the transition between different states. These changes were characterized within milliseconds to the second interval. The imaged lentivirus particles carrying only a single FRET-paired dye-labeled SARS-CoV-2 spike protomer among unlabeled wild-type spike proteins on a prism-based TIRF microscope.

Protein labels were inserted before and after the receptor binding motif of spike variants at specific positions to introduce dyes. Their analysis showed that D614G mutations would move the conformation from the “all-RBD-down” conformation, inaccessible to ACE2, to other conformations that would allow binding to occur. This is supported by several studies showing increased transmission of variants carrying D614G compared to wild type. Examination of the changes that E484K and N501Y can cause revealed that spike proteins in variants carrying these mutations were more likely to change conformation and more likely to switch to an ‘all-RBD-up’ conformation than any other.

Conclusion

The authors highlight the importance of their study to understand how these mutations affect the behavior and functionality of the adder protein, especially as many concern variants now share some of the more dangerous mutations that can increase transmissibility or help aid in immune evasion.

As expected, they discovered that the D614G mutation showed signs of increased infectivity compared to the wild-type strain. It helped to discover how the mutation affected the altered conformations of the spike protein trimmer.

They also helped reveal which mutations changed the conformation from the mostly ‘all -RBD -down’ – a closed conformation that helps prevent the host’s immune system from attacking the virus – to a more open conformation that is better for rapid growth infection and increased transmission.

In addition to this, the researchers showed that the E484K mutations increase the binding affinity of the spike protein by helping to change the conformation to a more open state as well as helping with immune evasion by creating an electrostatic charge that makes neutralization of antibodies less likely to bind to RBD.

The researchers claim that SARS-CoV-2 now shows an altered survival strategy, which has been chosen for mass vaccination programs, where strains showing immune evasion and rapid transmission have an evolutionary advantage.

*Important message

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and therefore should not be considered as crucial, guide clinical practice / health-related behavior or be treated as established information

Journal reference:

Yang, Z. et al. (2021) “SARS-CoV-2 variants exhibit increased kinetic stability of open spike conformations as an evolutionary strategy”. bioRxiv. doi: 10.1101 / 2021.10.11.463956.

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