The influence of epistatic interactions on the ACE2 affinity within the SARS-CoV-2 Omicron variant
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In a current examine posted to the bioRxiv* preprint server, researchers assessed the influence of epistatic interactions on the angiotensin-converting enzyme-2 (ACE2) affinity within the extreme acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant.

Study: Compensatory epistasis maintains ACE2 affinity in SARS-CoV-2 Omicron BA.1. Image Credit: Kateryna Kon/Shutterstock


Various research have investigated the results of mutations within the SARS-CoV-2 Omicron variant on ACE2 affinity in addition to antibody binding. These research give attention to the influence of single mutations on solely explicit genetic backgrounds. However, intensive analysis is required to know the interactions between combos of mutations present in Omicron and their influence on immune evasion and ACE2 affinity.

About the examine

In the current examine, researchers mapped the epistatic interactions incident between mutations current within the receptor-binding area of the SARS-CoV-2 Omicron BA.1 sublineage in comparison with these within the Wuhan pressure.

The crew employed a combinatorial meeting method to develop a plasmid library comprising all possible combos of the 15 mutations noticed within the BA.1 RBD. This library included all of the evolutionary intermediates doable between the BA.1 and the Wuhan RBDs. The crew used a technique primarily based on sequencing and high-throughput circulate cytometry known as Tite-Seq to estimate the binding affinities (OkD,app) of all of the doable viral RBD variants to the human ACE2. Furthermore, a normal biochemical mannequin of epistasis was match for the examine knowledge.


The examine outcomes confirmed that every one the 32,768 SARS-CoV-2 RBD intermediates doable between the Wuhan pressure and the Omicron BA.1 variant had a detectable affinity towards ACE2 with a OkD,app between 0.1 μM and 0.1 nM. The BA.1 RND had a three-fold enhance in binding affinity in comparison with that of the Wuhan pressure.

However, virtually 60% of the intermediate RBD sequences displayed weaker ACE2-binding affinity than that noticed for the Wuhan pressure. This was as a result of many of the BA.1 mutations had both a impartial or a deleterious impact on the affinity of ACE2 in many of the genetic backgrounds. This was very true for mutations similar to G446S, K417N, Q493R, Y505H, and G496S, amongst which 4 had been concerned within the immune evasion from a number of courses of monoclonal antibodies. 

While most of the BA.1 mutations lower ACE2 affinity, the interactions noticed between these mutations end result within the enhance of BA.1 affinity to ACE2. These mutations had been discovered to be extra deleterious for ACE2 affinity within the presence of some different mutations; nonetheless, these mutations show to be both impartial or useful when a number of different mutations are current.

The crew additionally noticed that though many of the 15 RBD mutations lower affinity to ACE2 within the Wuhan pressure background, these mutations are typically much less deleterious and extra advantageous within the Omicron background. This confirmed that the Omicron BA.1 RBD displayed a extra sturdy ACE2 affinity regardless of comprising mutations that individually lower ACE2 affinity because of the deleterious results of the mutations mitigated by epistatic interactions between the mutations.

The crew discovered that the linear results of the person mutations had been related to the contact floor space of ACE2 to the corresponding residue. The higher-order coefficients inferred from the biochemical technique confirmed sturdy compensatory interactions that mitigated the affinity-reducing results of the person mutations. The extent of those interactions was just like that noticed for the linear results, whereas the epistatic interactions famous had been extremely optimistic. This indicated that mutations that lowered ACE2 affinity had grow to be much less deleterious with respect to backgrounds with different compensatory mutations.

The epistatic interactions additionally eradicated the sturdy deleterious influence of the mutations concerned in antibody escape. The crew additionally discovered that the G446S, K417N, Q493R, Y505H, and G496S mutations had a unfavourable linear impact on viral affinity to ACE2; nonetheless, this impact was discovered to be very uncommon throughout the SARS-CoV-2 phylogeny. This prompt that sustaining ACE2 affinity might be an vital attribute of viral health; therefore, these mutations had been most certainly chosen in opposition to.

The crew additionally discovered that mutations having unfavourable results on ACE2 affinity mitigated by epistatic interactions with N501Y had been enriched amongst all SARS-CoV-2 strains that even have N501Y. This additional prompt that not less than just a few pairwise epistatic interactions had been current amongst different viral backgrounds.  


To summarize, the examine findings confirmed that the evolution of antibody escape within the SARS-CoV-2 Omicron BA.1 sublineage was doable with out decreasing ACE2 binding because of the compensatory epistatic interactions occurring with different mutations. The examine confirmed that high-order patterns of epistasis had been important for viral evolution involving adaptive occasions similar to immune evasion. The researchers consider that the era of particular combinatorial landscapes might assist perceive the overall patterns of epistasis accountable for viral evolution.  

*Important discover

bioRxiv publishes preliminary scientific studies that aren’t peer-reviewed and, due to this fact, shouldn’t be considered conclusive, information scientific apply/health-related habits, or handled as established data.

Journal reference:

  • Moulana, A. et al. (2022) “Compensatory epistasis maintains ACE2 affinity in SARS-CoV-2 Omicron BA.1”. bioRxiv. doi: 10.1101/2022.06.17.496635. material/10.1101/2022.06.17.496635v1

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