SARS-CoV-2 spike protein mutations

SARS-CoV-2 stands for Severe Acute Respiratory Syndrome - Corona Virus 2. The SARS-CoV-2 binding to the ACE-2 receptors on host cells causes COVID-19 (COrona VIrus Disease 2019). SARS-CoV-2 was numbered "2" because another coronavirus, fusion between the virus and host cell membranes. The genes of SARS-CoV-2 are in Details. Viruses with RNA genomes tend to mutate faster than do viruses with DNA genomes. For example, a new Details vaccine is needed every year due to mutations, and a single drug against 3- and 1-letter amino acid abbreviations quickly becomes ineffective due to mutations. It is no surprise that SARS-CoV-2 is mutating.

This page has not been updated since the greek letter terminology was introduced for variants, and it has not been updated since mid-2021.

spinqualitylabelsall models Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Spike Protein The spike protein (gene S) of SARS-CoV-2 plays a crucial role in attachment to host cells, by binding to the ACE-2 receptors on host cells. Spike protein is also the key player in fusion between the virus and host cell membranes, which delivers the virus genes into the cell, initiating infection. Spike protein is a homotrimer assembled from 3 sequence-identical protein chains, here pink, green, and blue. Mutations of concern in B.1.1.7 (black): see details below. (Show 4 B.1.1.7 mutations.) Amino acids that bind ACE-2 (Details). Furin cleavage site for priming (Details). Rotate to view the animation from all sides (drag to rotate). Zoom the molecule with your mouse wheel, or Shift-Drag up/down. Click the green links to change the molecular scene: Scroll down in this frame. Mutant Lineages Emerging In December, 2020, scientists in the United Kingdom discovered that among thousands of mutations in SARS-CoV-2 detected in the UK and elsewhere, coronavirus with a particular set of mutations appeared to be rapidly becoming the predominant lineage for new infections in parts of England. This lineage is termed B.1.1.7 or VOC 202012/01. Among more than 700 defined lineages it is the first globally distributed, well characterized mutant lineage recognized late in the pandemic (see Note 1). In late December, 2020, there was news from South Africa of another lineage becoming prevalent there, termed 501Y.V2, 501.V2, or B.1.351. In December, 2020, many scientists believed that B.1.1.7 is more contagious, but there remained some uncertainty, since the increase in B.1.1.7 could also be related to founder effects or variations in human behaviors in regions of England. However, by early January, 2021, it appeared very likely that B.1.1.7 and 501Y.V2 are more contagious. In January, 2021, lineage B.1.429 with mutation L452R was reported to be expanding rapidly in Northern California, USA. From late 2020 into early 2021, this lineage expanded from 4% of samples to 25%. Also in January, 2021, the lineage P.1 was found to have increased rapidly in Manaus, Brazil. P.1 has 10 mutations in the spike protein, including 3 in common with the South African lineage 501Y.V2 (N501Y, K417N, and E484K). P.1 was found in the USA in January, 2021. In February, 2021, mutations at position 677 (Q677P, Q677H) were reported to have arisen independently (convergent evolution) in the south central and southwest USA, where they accounted for 28% (in Louisiana) and 11% (in New Mexico) of sequenced SARS-CoV-2 genomes by late January. Q677H is present in lineage B.1.525. B.1.617 was first detected in October, 2020. By the end of April, 2021, B.1.617 was predominant in India, where a devastating surge of COVID-19 was overwhelming hospitals. In addition to India, B.1.617 was identified in the USA, UK, and Singapore. Mutations Most Concerning B.1.1.7 Four mutations in the outer surface of the spike protein are of particular concern in B.1.1.7: 1. N501Y: Asn at sequence position 501 mutated to Tyr. (See 3- and 1-letter amino acid abbreviations.) This mutation is in the receptor-binding domain of spike protein, and increases binding affinity for ACE-2, the receptor that SARS-CoV-2 uses to enter and infect cells. 2 & 3: Deletion of His 69 and Val 70. These deletions are in a position likely to affect the ability of certain antibodies to block infection. However, since vaccination induces antibodies to many parts of the spike protein, these mutations alone are unlikely to reduce the effectiveness of the current vaccines (see below). These deletions have been useful in epidemiologic screening for B.1.1.7 without needing to sequence all samples. 4. P681H: Pro 681 to His. This mutation is in the furin cleavage site that primes spike protein. The effects of this mutation are not yet known. B.1.351 The B.1.351 lineage (also called 501Y.V2 or 501.V2) accounted for more than half of new cases in South Africa in late December, 2020. This lineage is also suspected to have a higher rate of transmission. Its mutations of greatest concern include one in common with B.1.1.7 (N501Y) plus two different mutations that are, like N501Y, in the receptor binding domain of the spike protein: N501Y plus K417N and E484K. These mutations also increase binding affinity for ACE2. Unlike B.1.1.7, 501Y.V2 retains His 69 and Val 70 (not deleted). B.1.429 The lineage including spike protein mutation L452R increased from 4% to 25% of samples in Northern California, USA, by mid-January, 2021. Position 452 is in the ACE2 receptor-binding region. L452R confers resistance to convalescent serum antibodies, but its effect on T cell immunity is not known. Q677P/H Sequence position 677 is close to the furin cleavage site at PRRAR (681-684). The consequences of these mutations are under investigation. B.1.617 The defining mutations in B.1.617 include L452R, P681R, and E484Q. L452R is present in B.1.429 the US "California" lineage, and confers resistance to convalescent serum antibodies. P681R occurs in B.1.1.7, is in the furin cleavage site and is suspected of increasing contagiousness. E484Q is similar to E484K, present in the "South African" lineage B.1.351 / 501Y.V2, and is thought to contribute to evasion of immunity. Vaccine Effectiveness Under Investigation While the mutations in B.1.1.7 seem unlikely to make current anti-COVID-19 vaccines less effective, there is more concern regarding the additional mutations in 501Y.V2. Unfortunately, poor management of COVID-19 and inconsistent therapy maneuvers have favored development of mutations that may evade the initial wave of vaccines. Antibodies in the blood of half of people who have recovered from COVID-19 are unable to neutralize 501Y.V2, but other forms of immunity, such as T-cells, may still be protective. On January 28, 2021, Novavax reported that its vaccine, which was 90% effective in the UK, was only 50% effective in South Africa, where ~90% of cases were 501Y.V2. The next day, Johnson and Johnson announced similar results. Experts believe that present vaccines could be modified for greater effectiveness against these mutants, if necessary, withinin a few months. Moderna began development of a vaccine modified to combat 501Y.V2 in January, 2021. On March 26, 2021, public health officials in the UK announced a plan to begin booster vaccinations in September with variant-adapted vaccines. South Africa announced stopping the use of its supply of Astra-Zenica vaccine February 7, 2021. This was based on a small trial limited to young participants showing only about 20% effectiveness at preventing mild disease from 501Y.V2. Whether this vaccine prevents severe disease from 501Y.V2 in older people remained unclear. Virulence Increase Uncertain An early report found that B.1.1.7 does not increase hospitalization or death compared to the wild type SARS-CoV-2. Later evidence raised a "realistic possibility" of increased mortality. An analysis of statistics in February, 2021, by the UK Government New and Emerging Respiratory Virus Threats Advisory Group (NERVTAG) concluded that "it is likely that infection with VOC B.1.1.7 is associated with an increased risk of hospitalisation and death". Morbidity and mortality for the other variant lineages remains under investigation. National Borders Temporarily Closed Being at the forefront of SARS-CoV-2 science may have caused unnecessary problems for the UK. Shortly after B.1.1.7 was reported, France closed its borders to the UK. This caused stranding of truck drivers who are citizens of EU countries shortly before Christmas, and concerns about food supplies. Mutant Lineages Are Already Widely Disseminated However, even in mid-December, 2020, it seemed likely that B.1.1.7 or similar lineages were already spreading in many countries around the world -- whether they were imported or arose semi-independently. Reuters reported "Cases of the new strain have also been detected in some other countries, including Denmark and Italy. Experts said the prevalence in Britain might be down to better detection." John Edmunds (Professor of Infectious Disease Disease Epidemiology, London School of Hygiene and Tropical Medicine) noted that the UK has "one of the most comprehensive and sensitive molecular surveillance systems in the world and that allowed us to pick up this strain relatively quickly." He refers to the UK's COVID-19 Genomics Consortium (COG-UK). In contrast to the UK, the USA has done far less SARS-CoV-2 genome sequencing, leaving the spread of variants in the USA largely unknown. By the end of December, 2020, B.1.1.7 had been detected in at least 18 countries, plus the United States. By January 18, 2021, B.1.1.7 infections were detected in 20 states of the United States. By mid-February, 2021, B.1.1.7 was detected in 83 countries. Children, not yet vaccinated, are a dangerous reservoir of variants, according to evidence presented in May, 2021.

Movies for Slides

The movie at right (a multi-GIF, not interactive) can be dropped into a slide (Powerpoint, slides.google.com, libre office, etc.). It will animate when the slide is projected ("slide show" mode). This shows the ACE-2, whereas the interactive scenes above show the static open conformation. The scenes above show all atoms, while the movie shows only alpha carbons. As above for lineage B.1.1.7: each chain of the homo-trimer is a different color; Four mutations (black); ACE2 binding site; furin cleavage site. To DOWNLOAD these files, right click, then save link as:

• 464 pixels, HIGH RESOLUTION, 6.9 MB (not shown).
• 300 pixels (low resolution, 3.1 MB) shown at right.

Please credit Proteopedia.Org in accord with our license, and Wrobel and coworkers for their cryo-EM structures.

Acknowledgements

Thanks to Shoshana Wodak, Iddo Friedberg, S. Krishnaswamy and Joel Sussman for suggestions that improved this article. Eric Martz wishes to thank Jaime Prilusky and Joel Sussman for their constant efforts over more than a decade that have made Proteopedia what it is today. Thanks also to the newer members of the Proteopedia:Team.

Update History

This article was initially posted December 22, 2020. Subsequent updates:

• December 23, 2020: Full name of SARS corrected. Citation added.
• December 24, 2020: Added further evidence of the international pre-eminence of the UK coronavirus sequencing consortium. Added Acknowledgements.
• December 25, 2020: Added two citations and added mention of the South African lineage without specific mutations.
• December 27, 2020: Added this section Update History. Named and visualized the specific mutations of concern in the South African lineage 501Y.V2, with a new citation.
• December 29, 2020: Added two references documenting detection of B.1.1.7 in at least 19 countries.
• December 30, 2020: Added study showing no increased hospitalization or death for B.1.1.7 compared to wild type SARS-CoV-2.
• January 4, 2021: Added evidence that the mutant lineages are more contagious.
• January 5, 2021: Added a new subsection about concerns over vaccine effectiveness, with two new references.
• January 6, 2021: Cited analysis of events that have inadvertently favored mutations to evade vaccine effectiveness.
• January 7, 2021: Added a preprint showing that some of the mutations in B.1.1.7 and 501Y.V2 increase binding affinity between the spike protein and its receptor ACE2.
• January 9, 2021: Added alternate name B.1.351 for 501Y.V2.
• January 20, 2021: B.1.1.7 detected in 20 US states. Added L452R lineage.
• January 25, 2021: Convalescent plasma often ineffective against 501Y.V2 and Moderna developing variant vaccine.
• January 27, 2021: Mentioned D614G that became prevalent during the onset of the pandemic. See Note 1. Cited definition of lineage. Mentioned epidemiological screening utility of deletions H67,V70. Mentioned Brazilian variant P.1.
• January 28, 2021: Updated evidence on B.1.1.7 mortality.
• January 29, 2021: Cited a report by Novavax of lower vaccine effectiveness in South Africa, and evidence that the USA is doing far too little virus genome sequencing.
• January 30, 2021: Cited Johnson & Johnson's vaccine trial results posted January 29.
• February 8, 2021: Added halting of use of Astra-Zenica vaccine in South Africa. Changed most mentions of 501.V2 to 501Y.V2 as this terminology seems to have become predominant.
• February 16, 2021: Cited mutations at position 677. Cited evidence for increased virulence of B.1.1.7.
• February 17, 2021: Cited list of >700 defined lineages. Used lineage nomenclature more consistently, where feasible. B.1.1.7 now in 83 countries.
• March 30, 2021: Cited announcement that the UK will start variant-adapted boosters in September, 2021.
• May 4, 2021: Added information about B.1.617 and the surge in India with several new references.
• May 24, 2021: Added evidence that unvaccinated children are a reservoir of variants.

See Also

• Coronavirus Disease 2019 (COVID-19) which lists numerous articles in Proteopedia concerning specific genes and proteins in SARS-CoV-2.
• SARS-CoV-2 protein S priming by furin
• SARS-CoV-2 spike protein fusion transformation

Notes

Note 1. The mutation D614G became predominant very early in the pandemic, before April, 2020. It is not discussed above, as the purpose of this article is to show mutations that occurred months into the worldwide pandemic, after vaccine development was well underway.

Proteopedia Page Contributors and Editors (what is this?)

Eric Martz