Computational comparison of SARS-CoV-2 Delta and Omicron variant binding affinity with ACE2

The Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has recently arisen in South Africa. It has induced a drastic response in many nations worldwide, with countries once again closing borders and re-introducing some of the restrictions seen regularly in the last two years. With a record number of mutations, most situated within the receptor-binding domain (RBD) of the spike protein, relatively little is known about the Omicron variant. Researchers from the Management and Science University in Malaysia have used computational tools to investigate the new variant.

Study: Omicron and Delta Variant of SARS-CoV-2: A Comparative Computational Study of Spike protein. Image Credit: FOTOGRIN/Shutterstock

A preprint version of the study is available on the bioRxiv* server while the article undergoes peer review.

The study

The ProtParam online tool captured the different strain's molecular weight. This tool calculates molecular weight, theoretical pI, amino acid composition, atomic composition, extinction coefficient, anticipated half-life, instability index, aliphatic index, and grand average of hydropathicity (GRAVY). To predict the secondary structure, a program called GOR IV was used. Intrinsic disorder regions (IDRs), regions in which physiological contexts with an ensemble of conformations were predicted by PONDR, while protein stability was predicted using I-Mutant.

The researchers detected 30 mutations in the spike protein, half of which reside within the RBD. Detection of the RBD by angiotensin-converting enzyme 2 (ACE2) requires the T470-T478 loop and Y505. T478 is a mutation seen in both Delta and Omicron variants. While the wild-type variant has 1273 amino acids, the Delta and the Omicron variants both have less, 1271 and 1270, respectively.

A protein's isoelectric point (pI) is the pH value when the surface is charged, but the net charge is zero. Similar to pH, pI above 7 is alkaline, and below is acidic. The molecular weight of the wild-type variants is 141178.47, and it has a pI of 6.24. The Delta variant has a molecular weight of 140986.31 with a pI of 6.78, and the Omicron variant is 141328.11 with a pI of 7.14. The higher molecular weight of the Omicron variant is unusual, as it has fewer amino acids than both the wild-type and Delta variants.

Regarding stability scores, the researchers discovered that the stability across all spike proteins ranged between 32.8 and 34.7, slightly below the value of 40 that indicates a protein is structurally unsound. The aliphatic index measures thermostability, with higher ratings indicating better thermostability. The spike protein ranges from 84.5 to 84.95, indicating good stability. The low GRAVY score suggests that it is intrinsically hydrophilic.

Primary structure analysis reveals that the amino acids composition of the Omicron variant shows an increase in charged residues such as arginine, lysine, aspartic acid, and glutamic acid, suggesting that charged residues are exposed to greater degrees, and salt bridges can form more easily. Other amino acids that occur more regularly in the Omicron variant than the Delta variant include Phenylalanine and Isoleucine, suggesting that it is slightly more hydrophobic. Secondary structural analysis of the Omicron variant reveals a higher proportion of alpha-helices than the Delta variant but less extended strand and random coil structures, leading to more structural stability.

Generally, disordered areas of viral protein are linked to viral pathogenicity and infectivity, and the Omicron variant has a less disordered area than both the Delta strain and the wild-type. The specific changes suggest a disorder change to order transition within the spike protein, which could be important for ACE2 binding. All of the mutations within the Delta variant are theorized to reduce stability, and the same appears to be true with the Omicron variant. Only N501Y bucks the trend.  N211I, Y50H, and N764K also appear to impair protein function, as do L452R and T478, found in the Delta strain.

The crystal structure of the spike RBD was isolated from ACE2 and used for protein-protein docking, revealing that the Omicron variant has the highest score and the Delta the lowest. This would suggest higher binding for ACE2 and more infectivity than the Delta variant. This is likely due to mutations at key residues such as K31, which is affected by the E484 mutation.


The authors highlight that their study provides valuable insight into the Omicron and Delta variants and the different mutations which drive them. The dynamic changes that can affect protein stability, ACE2 binding and infectivity were explored using computational tools and modeling. The researchers have provided a large amount of information that could be used to help researchers further investigate the new variant and predict how quickly it can spread and how much damage it could do.

*Important notice

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

Journal reference:
  • Kumar, S. et al. (2021) "Omicron and Delta Variant of SARS-CoV-2: A Comparative Computational Study of Spike protein". bioRxiv. doi: 10.1101/2021.12.02.470946.

Posted in: Medical Science News | Medical Research News | Disease/Infection News

Tags: ACE2, Amino Acid, Angiotensin, Angiotensin-Converting Enzyme 2, Arginine, Aspartic Acid, binding affinity, Coronavirus, Coronavirus Disease COVID-19, Enzyme, Glutamic Acid, Isoleucine, Lysine, Mutation, pH, Phenylalanine, Protein, Protein Stability, Receptor, Respiratory, SARS, SARS-CoV-2, Severe Acute Respiratory, Severe Acute Respiratory Syndrome, Spike Protein, Syndrome

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Written by

Sam Hancock

Sam completed his MSci in Genetics at the University of Nottingham in 2019, fuelled initially by an interest in genetic ageing. As part of his degree, he also investigated the role of rnh genes in originless replication in archaea.

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