Scanning the RBD-ACE2 molecular interactions in Omicron variant

Rath, Soumya Lipsa; Padhi, Aditya K.; Mandal, Nabanita

doi:10.1101/2021.12.12.472253

Cited by 11 publications

(16 citation statements)

References 20 publications

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“…The preprint of this study was the first in the literature to show via all-atom MD simulations the effect of the omicron BA.1 mutations on RBD-PD interactions and binding strength. Our findings have been supported with recent computational 17,18 and experimental studies 11,19-21 . There is currently no consensus regarding the exact binding energy of the BA.1 omicron variant S protein to ACE2.…”

Section: Discussionsupporting

confidence: 90%

“…Binding free energies ranging from −107.04 to −635.32 kcal/mol were reported by post-processing all-atom MD trajectories. 17,18 Furthermore, K D values ranging 25.3-38.9 nM were reported for the BA.1 omicron variant. 11,19–21 While these approaches report different K D values, consistent with our findings, they all estimate a higher binding strengths for RBD BA.1 compared to the RBD WT .…”

Section: Discussionmentioning

confidence: 96%

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Omicron BA.1 and BA.2 Variants Increase the Interactions of SARS-CoV-2 Spike Glycoprotein with ACE2

Golcuk

Yıldız

Gür

2021

Preprint

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The Omicron variant (B.1.1.529) comprises 30 mutations on the spike glycoprotein (S), 15 of which are located on its receptor-binding domain (RBD_Omicron). RBD interacts with the peptidase domain (PD) of angiotensin-converting enzyme 2 (ACE2) receptors and plays a critical role in the host cell entry of the virus. We performed all-atom simulations of the RBD_Omicron-PD in the presence of explicit water and ions. Simulations showed a considerably more extensive interactions network between RBD_Omicron and PD compared to RBD_WT, comprising a 250%, 10% and -25% change in the total number of salt bridges, hydrophobic interactions, hydrogen bonds at the S-ACE2 interface, respectively. Using the conformations sampled in each our MD trajectories, binding energies of two sets of RBD_WT-PD and four sets of RBD_Omicron-PD simulations were calculated via the Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA) method, estimating ~44% stronger binding energy for RBD_Omicron compared to RBD_WT. Our results suggest that an increase in the number of salt bridges in the S-ACE2 interface result in a higher binding strength of RBD to PD, which may result in a higher efficiency of the SARS-CoV-2 virus to infect host cells. Furthermore, RBD_Omicron exhibits a more dispersed interaction network on both sides of the RBD-PD interaction surface compared to WT.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 96%

Omicron BA.1 and BA.2 Variants Increase the Interactions of SARS-CoV-2 Spike Glycoprotein with ACE2

Golcuk

Yıldız

Gür

2021

Preprint

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“…Our results add to the evidence (Iketani et al, 2022;Liu et al, 2022) that single amino acid changes may confer full resistance to neutralizing antibodies. In comparison, mutation of E484A that has also been observed in other SARS-CoV-2 VOCs and was suggested to be associated with immune-escape (Rath et al, 2022) had only marginal effects on neutralization sensitivity.…”

Section: Discussionmentioning

confidence: 81%

Determinants of Spike Infectivity, Processing and Neutralization in SARS-CoV-2 Omicron subvariants BA.1 and BA.2

Pastorio

Zech

Noettger

et al. 2022

Preprint

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The SARS-CoV-2 Omicron variant rapidly outcompeted other variants and currently dominates the COVID-19 pandemic. Its enhanced transmission, immune evasion and pathogenicity is thought to be driven by numerous mutations in the Omicron Spike protein. Here, we examined the impact of amino acid changes that are characteristic for the BA.1 and/or BA.2 Omicron lineages on Spike function, processing and susceptibility to neutralization. Individual mutations of S371F/L, S375F and T376A in the ACE2 receptor-binding domain as well as Q954H and N969K in the hinge region 1 impaired infectivity, while changes of G339D, D614G, N764K and L981F moderately enhanced it. Most mutations in the N-terminal region and the receptor binding domain reduced sensitivity of the Spike protein to neutralization by sera from individuals vaccinated with the BNT162b2 vaccine or therapeutic antibodies. Our results represent a systematic functional analysis of Omicron Spike adaptations that allowed this SARS-CoV-2 variant to overtake the current pandemic.

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“…There are several experimental and computational studies which clearly show the cause of a high transmission of the Omicron variant and its immune evasion [22][23][24][25] . The increase in the binding of the SARS-CoV-2 receptor ACE2 with the RBD is the main cause of the enhanced transmission of the Omicron variant.…”

Section: Introductionmentioning

confidence: 99%

“…In another study, it was shown that the mutations in the Omicron RBD yields more contacts, hydrogen bonds and buried surface area at the interface of spike RBD and ACE-2 receptor, as compared to the original strain 24 . Rath et al 22 reported 2.5 times stronger binding between the mutated residues and ACE-2 receptor together with a much relaxed dynamics of the complex, as compared to the wild type.…”

Section: Introductionmentioning

confidence: 99%

Structural basis of Omicron immune evasion: A comparative computational study of Spike protein-Antibody interaction

Contractor

Globisch

Swaroop

et al. 2022

Preprint

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The COVID-19 pandemic has caused more than 424 million infections and 5.9 million deaths so far. The vaccines used against SARS-COV-2 by now have been able to develop some neutralising antibodies in the vaccinated human population and slow down the infection rate. The effectiveness of the vaccines has been challenged by the emergence of the new strains with numerous mutations in the spike (S) protein of SARS-CoV-2. Since S protein is the major immunogenic protein of the virus and also contains Receptor Binding Domain (RBD) that interacts with the human Angiotensin-Converting Enzyme 2 (ACE2) receptors, any mutations in this region should affect the neutralisation potential of the antibodies leading to the immune evasion. Several variants of concern (VOC) of the virus have emerged so far. Among them, the most critical are Delta (B.1.617.2), and recently reported Omicron (B.1.1.529) which have acquired a lot of mutations in the spike protein. We have mapped those mutations on the modelled RBD and evaluated the binding affinities of various human antibodies with it. Docking and molecular dynamics simulation studies have been used to explore the effect of the mutations on the structure of the RBD and the RBD-antibody interaction. The analysis shows that the mutations mostly at the interface of a nearby region lower the binding affinity of the antibody by ten to forty percent, with a downfall in the number of interactions formed as a whole and therefore, it implies the generation of immune escape variants. Notable mutations and their effect was characterised by performing various analyses that explain the structural basis of antibody efficacy in Delta and a compromised neutralisation effect for the Omicron variant. Our results pave the way for robust vaccine design that can be effective for many variants.

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Scanning the RBD-ACE2 molecular interactions in Omicron variant

Cited by 11 publications

References 20 publications

Omicron BA.1 and BA.2 Variants Increase the Interactions of SARS-CoV-2 Spike Glycoprotein with ACE2

Omicron BA.1 and BA.2 Variants Increase the Interactions of SARS-CoV-2 Spike Glycoprotein with ACE2

Determinants of Spike Infectivity, Processing and Neutralization in SARS-CoV-2 Omicron subvariants BA.1 and BA.2

Structural basis of Omicron immune evasion: A comparative computational study of Spike protein-Antibody interaction

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