In a recent study posted to the bioRxiv* preprint server, researchers analyzed the effects of mutations of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) Omicron variant at the atomic level.
Study: Mutations of Omicron variant at the interface of the receptor domain motif and human angiotensin-converting enzyme-2. Image Credit: Lightspring/Shutterstock
This news article was a review of a preliminary scientific report that had not undergone peer-review at the time of publication. Since its initial publication, the scientific report has now been peer reviewed and accepted for publication in a Scientific Journal. Links to the preliminary and peer-reviewed reports are available in the Sources section at the bottom of this article. View Sources
The impact of the coronavirus disease 2019 (COVID-19) pandemic on global health and economics has been massive. The emergence of novel SARS-CoV-2 mutants throughout the pandemic has been detrimental as they present with enhanced pathogenic characteristics. Global COVID-19 cases have increased substantially due to the novel Omicron variant since late 2021.
Some of the striking features of the Omicron variant include high transmissibility, immune evasion, and decreased vaccine efficiency attributed to a large number of its mutations, most notable ones being present in the receptor-binding domain (RBD) of the spike (S) protein. The S protein is required for viral entry in host cells by attaching to the angiotensin-converting enzyme 2 (ACE2) receptor. At the interface between viral S and human ACE2 is the receptor-binding motif (RBM) of the S RBD that acts as the main functional motif, and as per reports, 10 of the 15 RBD mutations of the Omicron variant are found in the RBD.
The study
In the present study, the researchers investigated the effects of mutations on the amino acid (AA) interactions at the interface between ACE2 and RBM of the wildtype (WT) and mutant (Omicron variant) viruses. The authors implemented an ab initio quantum mechanical calculation and developed a novel AA-AA bond pair unit (AABPU) concept.
The AA interactions were studied between RBM and a region of human ACE2, i.e., 71 AAs (S438 to Y508) of RBM and 117 AAs (S17 to I88 and G319 to T365) of ACE2. Ten RBM sites were mutated using Dunbrack backbone-dependent rotamer library with UCSF Chimera.
The strength of a bond between a pair of atoms, i.e., bond order, is measured in an orthogonalized linear combination of atomic orbitals (OLCAO); instead, the researchers implemented bond order calculation for a pair of amino acids and termed it amino acid-amino acid bond pair (AABP). AABP has been described as a fundamental biological unit and referred to as AABPU. According to the authors, both covalent interactions and hydrogen bonding between amino acids can be evaluated with this approach (AABP). Moreover, AABP can quantify nearest neighbor (NN) pairs and non-local (NL) interactions from non-NN pairs.
Findings
The team observed that the AA substitutions in the mutant (Omicron) RBM caused substantial changes in the shape, orientation, and number of NL AAs. For the Q498R substitution, the number of NL AAs increased from 11 (WT) to 15 (Omicron), and in E484A mutation, it decreased from four (WT) to two (mutant). Mutations increased the total AABP for six out of 10 sites (G446S, S477N, T478K, Q493R, Q498R, and N501Y). Eight mutated RBM sites (except Q493R and E484A) occupied larger volumes than the corresponding WT RBM sites; In the Q498R substitution, the volume of the AABPU increased by 56.3% to 2346 Å3, and a similar increase of about 34% was observed for the surface area of the AABPU.
The evaluation of the electronic structure identified no major changes in the total density of states between the WT and Omicron RBM. A total of 19 different types of bonds were noted in the WT RBM, while 18 different bond types were observed in the mutant RBM due to the complete absence of the N-Na bonds in the Omicron RBM.
At the interface of RBM and ACE2, seven AAs from the WT RBM interacted with ACE2 AAs, whereas only six from the mutated RBM formed bonds with the host ACE2. Of these six AAs, five AAs showed higher AABP values in bond interactions with ACE2, which is indicative of enhanced binding of the mutant RBM to ACE2. Interestingly, unmutated sites in the Omicron RBM showed changes in bonding with ACE2, three sites (L455, A475, and Y489) showed higher AABP values than the WT RBM, one site (T500) had a lower AABP value, and another site (Y449) failed to form a bond with ACE2.
Mutated RBM sites showed differences in the partial charge (PC) of AAs compared to the corresponding WT sites. Nine sites of the Omicron RBM showed a positive increase in the PC. The overall PC of the 10 RBM sites was 1.245 e- for the WT RBM and 6.745 e- for the mutant RBM.
Conclusions
To summarize the findings, the present study provided interesting insights into the interactions of AAs at the interface between SARS-CoV-2 spike and human ACE2 receptors. The authors introduced AABPU as a quantitative unit of AABP and demonstrated that the RBM mutations enhance the binding affinity of the viral AAs to the host ACE2.
Unmutated RBM sites of the Omicron variant also showed an increase in binding interactions to ACE2, suggesting that mutations affect the bonding of unmutated sites as well. The mutated RBM showed a massive increase in the overall positive PC, which has been suggested to enhance the overall infectivity of the Omicron variant. Taken together, the findings elucidated the AA interactions between WT and mutant RBM to ACE2 at an atomic scale, and this approach can help understand and characterize novel SARS-CoV-2 variants in the future.
This news article was a review of a preliminary scientific report that had not undergone peer-review at the time of publication. Since its initial publication, the scientific report has now been peer reviewed and accepted for publication in a Scientific Journal. Links to the preliminary and peer-reviewed reports are available in the Sources section at the bottom of this article. View Sources
Article Revisions
- May 11 2023 - The preprint preliminary research paper that this article was based upon was accepted for publication in a peer-reviewed Scientific Journal. This article was edited accordingly to include a link to the final peer-reviewed paper, now shown in the sources section.
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