Scientists study mutations in the SARS-CoV-2 receptor-binding domain


In a recently published study in the Drug discovery today In the journal, researchers assessed the various worrisome mutations in the receptor-binding domain (RBD) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

To learn: Mutation informatics: SARS-CoV-2 receptor binding domain of the spike protein. Credit: PHOTOCREO Michal Bednarek/Shutterstock

Traditional approaches to drug discovery have failed to develop effective treatments against the different strains of SARS-CoV-2. The emerging mutant viral strains have highlighted the need for new drugs against all SARS-CoV-2 variants.

mutational informatics

The successful application of target-based drug design has motivated researchers to use these techniques to develop potential new antiviral agents against SARS-CoV-2 wild-type and mutant strains. Various researchers have analyzed the sequences and 3D structures corresponding to wild-type and mutant targets using multiple bioinformatics tools to understand their altered geometry and physicochemical properties. Such an analysis of physico-chemical aspects related to mutations in the binding pocket of the target proteins helps to design effective molecules against the different SARS-CoV-2 strains.

The informatics data related to point mutations predicted that viral mutations such as T478K, N501Y, Q498R and Q493R lead to a stabilization of the binding interactions that occur between RBD and angiotensin converting enzyme-2 (ACE-2). These mutations have been found to significantly affect the isoelectric point, polarity and hydropathy index associated with the mutant residues including Q498R, Q493R and L452R belonging to the omicron and delta variants of SARS-CoV-2. The mutations Q498R and Q493R from the Omicron variant were responsible for the increased affinity between ACE2 and RBD.

The researchers also observed that arginine contributed significantly to the observed high affinity between ACE2 and RBD and could be the cause of viral pathogenicity. The Q498R and Q493R mutations were also likely the reason for Omicron’s high transmissibility. The team also found that replacing the amino acids present in the target protein with amino acids with different physicochemical properties led to changes in the mechanistic interaction between ACE2 and RBD.

The team observed that the T478K mutation played an essential role in reshaping and stabilizing the receptor binding motif (RBM) loop, further enhancing ACE2 interaction. Furthermore, the structural configuration of the Omicron spike trimer with ACE2 revealed that Omicron had a six- to nine-fold increase in ACE2 affinity due to the additional mutations. Furthermore, the Q498R, N501Y and T478K mutations increased the interaction affinity between ACE2 and RBD. The study also showed that the omicron RBD was less thermodynamically stable but more dynamic compared to the wild-type RBD.

One study examined the main interacting residue present between ACE2 and viral RBD according to molecular dynamics (MD) simulation results. The hotspot residues in residues were found to be K417, Y449, 172 F486, N487, L455, F456, Y489, Q493, Y495, Q498, T500, N501 and Y505, while ACE2 hotspots were K353, K31, D30, 175 D355 were. H34, D38, Q24, T27, Y83, Y41 and E35. In the RBDs corresponding to the SARS-CoV-2 alpha and delta variants, the binding interactions are different due to the N501Y mutation. In addition, it was found that the alpha variant is more tightly bound to ACE2 compared to the beta variant and the wild-type strain. The study also found that in the beta variant, the K417N mutation decreased ACE2-binding affinity, while the E484K mutation increased it.

A study examining the influence of N501Y, E484K, L452R, S477N and N439K on the binding mechanism of RBD and ACE2 showed that N501Y, E484K and N493K increased RBD stiffness and RBM flexibility. In addition, L452R and S477N improved RBM flexibility while maintaining RBD flexibility compared to that in wild-type RBD. The study highlighted the importance of N439K and K417N for altered binding affinity between RBD and ACE2.

RBD-ACE2 interface as drug target

Various small molecules have been reported to act as inhibitors of SARS-CoV-2 entry as well as ACE2 binding. Among the inhibitors that prevent virus entry, oxazolecarboxamides blocked the binding interactions between ACE2 and the aSARS-CoV-2 protein RBD. A study suggested that oxazolecarboxamides can inhibit the bound and unbound interactions along with the conformational flexibility correlating with the interaction.


The study results highlighted new ideas related to the design and development of inhibitors against infections caused by the SARS-CoV-2 wild-type strains or the mutated variants. The researchers believe that examining the physicochemical aspects of each mutation is essential to understanding its virulence as well as its transmissibility.

Magazine reference:

Saroj Verma, Vaishali M Patil, Manish K Gupta. (2022). Mutation informatics: SARS-CoV-2 receptor binding domain of the spike protein. Drug discovery today. doi:


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