SARS-CoV-2 Omicron RBD shows weaker binding affinity than the currently dominant Delta variant to human ACE2.
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ABSTRACT:
SUBMITTER: Wu L
PROVIDER: S-EPMC8727475 | biostudies-literature | 2022 Jan
REPOSITORIES: biostudies-literature
Publications
SARS-CoV-2 Omicron RBD shows weaker binding affinity than the currently dominant Delta variant to human ACE2.
Wu Leyun L Zhou Liping L Mo Mengxia M Liu Tingting T Wu Chengkun C Gong Chunye C Lu Kai K Gong Likun L Zhu Weiliang W Xu Zhijian Z
Signal transduction and targeted therapy 20220105 1
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Project description:The emergence of new SARS-CoV-2 variants poses a threat to the human population where it is difficult to assess the severity of a particular variant of the virus. Spike protein and specifically its receptor binding domain (RBD) which makes direct interaction with the ACE2 receptor of the human has shown prominent amino acid substitutions in most of the Variants of Concern. Here, by using all-atom molecular dynamics simulations we compare the interaction of Wild-type RBD/ACE2 receptor complex with that of the latest Omicron variant of the virus. We observed a very interesting diversification of the charge, dynamics and energetics of the protein complex formed upon mutations. These results would help us in understanding the molecular basis of binding of the Omicron variant with that of SARS-CoV-2 Wild-type.
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Project description:The SARS-CoV-2 claimed millions of lives, globally. Occurring from Wuhan (wild type) in December, 2019, it constantly mutated to Omicron (B.1.1.529), the predecessor to Delta. Omicron having ~ 32 spike mutations has variable infectivity-multiplicity-immuno-invasive properties. Understanding of its mutational effect on ACE2-binding/disease severity and developing preventive/therapeutic strategies are important. The binding affinities of Wuhan/Delta/Omicron spikes (PDB/GISAID/SWISS-MODEL) were docked (HADDOCK2.4) with ACE2 and compared by competitive-docking (PRODIGY). The protein structural stability was verified by kinetic-data/Ramachandran-plot (Zlab/UMassMedBioinfo). After several trials, a 59 amino acid (453ARG-510VAL) peptide-cut (Expasy-server) of the wild-type spike RBD with some desired mutants (THR500SER/THR500GLY/THR500ALA/THR500CYS) was blindly/competitively docked (PyMOL-V2.2.2) to block the Omicron-ACE2 binding. We examined molecular dynamic simulation (iMOD-server, with 9000 cycles/300 k-heating/1 atm pressure for system equilibration for 50 ns-run) of ACE2 and two CUTs with different SARS-CoV-2 variants. The binding-affinity of Omicron-ACE2 is slightly higher than the rest two in competitive docking setup. During individual (1:1) docking, Omicron showed little higher than wild type but much weaker binding affinity than Delta. Competitive docking suggests ten H-bonding (1.3-2.4 Å) with highly favorable energy values/Van-der-Walls-force/Haddock score for more stable-binding of Omicron-RBD with ACE2. Blind docking of different CUTs (wild/mutants) and Omicron to ACE2 completely rejected the Omicron-RBD from ACE2-target. The best blocking/binding affinity of -16.4 and -13 kcal/mole were observed in the case of THR500SER and THR500GLY, respectively, with multiple H-bonding 1.9-2.2 Å. These are supported by the MD-simulation results. So, the spike binding affinities were Delta > Omicron > wild in 1:1 docking with ACE2. Considering the wild type is non-existing nowadays, Omicron showed less ACE2 binding properties. The 59 cut of spike-RBD and its mutant THR500SER/THR500GLY may be further screened as universal blockers of this virus.Supplementary informationThe online version contains supplementary material available at 10.1007/s11224-022-02022-x.
| S-EPMC9362541 | biostudies-literature
Project description:The SARS-CoV-2 Omicron variant containing 15 mutations, including the unique Q493R, in the spike protein receptor binding domain (S1-RBD) is highly infectious. While comparison with previously reported mutations provide some insights, the mechanism underlying the increased infections and the impact of the reversal of the unique Q493R mutation seen in BA.4, BA.5, BA.2.75, BQ.1 and XBB lineages is not yet completely understood. Here, using structural modelling and molecular dynamics (MD) simulations, we show that the Omicron mutations increases the affinity of S1-RBD for ACE2, and a reversal of the unique Q493R mutation further increases the ACE2-S1-RBD affinity. Specifically, we performed all atom, explicit solvent MD simulations using a modelled structure of the Omicron S1-RBD-ACE2 and compared the trajectories with the WT complex revealing a substantial reduction in the Cα-atom fluctuation in the Omicron S1-RBD and increased hydrogen bond and other interactions. Residue level analysis revealed an alteration in the interaction between several residues including a switch in the interaction of ACE2 D38 from S1-RBD Y449 in the WT complex to the mutated R residue (Q493R) in Omicron complex. Importantly, simulations with Revertant (Omicron without the Q493R mutation) complex revealed further enhancement of the interaction between S1-RBD and ACE2. Thus, results presented here not only provide insights into the increased infectious potential of the Omicron variant but also a mechanistic basis for the reversal of the Q493R mutation seen in some Omicron lineages and will aid in understanding the impact of mutations in SARS-CoV-2 evolution.
| S-EPMC10006685 | biostudies-literature
Project description:The rise of SARS-CoV-2 variants, with changes that could be related to an increased virus pathogenicity, have received the interest of the scientific and medical community. In this study, we evaluated the changes that occurred in the viral spike of the SARS-CoV-2 Omicron variant and whether these changes modulate the interactions with the angiotensin-converting enzyme 2 (ACE2) host receptor. The mutations associated with the Omicron variant were retrieved from the GISAID and covariants.org databases, and a structural model was built using the SWISS-Model server. The interaction between the spike and the human ACE2 was evaluated using two different docking software, Zdock and Haddock. We found that the binding free energy was lower for the Omicron variant as compared to the WT spike. In addition, the Omicron spike protein showed an increased number of electrostatic interactions with ACE2 than the WT spike, especially the interactions related to charged residues. This study contributes to a better understanding of the changes in the interaction between the Omicron spike and the human host ACE2 receptor.
| S-EPMC8779645 | biostudies-literature
Project description:The receptor-binding domain (RBD) is the essential part in the Spike-protein (S-protein) of SARS-CoV-2 virus that directly binds to the human ACE2 receptor, making it a key target for many vaccines and therapies. Therefore, any mutations at this domain could affect the efficacy of these treatments as well as the viral-cell entry mechanism. We introduce ab initio DFT-based computational study that mainly focuses on two parts: (1) Mutations effects of both Delta and Omicron variants in the RBD-SD1 domain. (2) Impact of Omicron RBD mutations on the structure and properties of the RBD-ACE2 interface system. The in-depth analysis is based on the novel concept of amino acid-amino acid bond pair units (AABPU) that reveal the differences between the Delta and/or Omicron mutations and its corresponding wild-type strain in terms of the role played by non-local amino acid interactions, their 3D shapes and sizes, as well as contribution to hydrogen bonding and partial charge distributions. Our results also show that the interaction of Omicron RBD with ACE2 significantly increased its bonding between amino acids at the interface providing information on the implications of penetration of S-protein into ACE2, and thus offering a possible explanation for its high infectivity. Our findings enable us to present, in more conspicuous atomic level detail, the effect of specific mutations that may help in predicting and/or mitigating the next variant of concern.
| S-EPMC9456519 | biostudies-literature
Project description:BackgroundCOVID-19 is still an important public health problem. After a pandemic, there is already new emerging mutant type of COVID-19. Starting from mutant with few mutations, the new mutant types with several mutations occur. Omicron variant is the new variant of concern that starts outbreak from Africa and might be the new problem worldwide.MethodPathogenesis may change as a result of molecular changes. An important possible effect of mutation is a change in binding affinity with receptor. Here, the authors performed a study to assess the effect of mutations of ACE2 receptor binding affinity in important COVID-19 variants, beta, delta and omicron variants.ResultsAccording to the analysis, change of binding affinity to receptor in each studied mutated variant comparing to classical wild type SARS CoV2 is observed.ConclusionThis exploratory research on changes in ACE2 receptor binding affinity revealed that changes do occur and may contribute to the pathophysiology. The omicron variation has a greater degree of alteration than the well-known significant variants, beta and delta. Rapid spread due to simpler transmission is envisaged as a result of affinity modification. Nevertheless, the authors only examined the affinity with bioinformatics analysis. It is different from experimental analysis, therefore, it may not real and further studies are required for confirmation.
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Project description:The coronavirus disease 2019 (COVID-19) pandemic continues worldwide with many variants arising, some of which are variants of concern (VOCs). A recent VOC, omicron (B.1.1.529), which obtains a large number of mutations in the receptor-binding domain (RBD) of the spike protein, has risen to intense scientific and public attention. Here, we studied the binding properties between the human receptor ACE2 (hACE2) and the VOC RBDs and resolved the crystal and cryoelectron microscopy structures of the omicron RBD-hACE2 complex as well as the crystal structure of the delta RBD-hACE2 complex. We found that, unlike alpha, beta, and gamma, omicron RBD binds to hACE2 at a similar affinity to that of the prototype RBD, which might be due to compensation of multiple mutations for both immune escape and transmissibility. The complex structures of omicron RBD-hACE2 and delta RBD-hACE2 reveal the structural basis of how RBD-specific mutations bind to hACE2.
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Project description:The currently circulating Omicron sub-variants are the SARS-CoV-2 strains with the highest number of known mutations. Herein, we found that human angiotensin-converting enzyme 2 (hACE2) binding affinity to the receptor-binding domains (RBDs) of the four early Omicron sub-variants (BA.1, BA.1.1, BA.2, and BA.3) follows the order BA.1.1 > BA.2 > BA.3 ≈ BA.1. The complex structures of hACE2 with RBDs of BA.1.1, BA.2, and BA.3 reveal that the higher hACE2 binding affinity of BA.2 than BA.1 is related to the absence of the G496S mutation in BA.2. The R346K mutation in BA.1.1 majorly affects the interaction network in the BA.1.1 RBD/hACE2 interface through long-range alterations and contributes to the higher hACE2 affinity of the BA.1.1 RBD than the BA.1 RBD. These results reveal the structural basis for the distinct hACE2 binding patterns among BA.1.1, BA.2, and BA.3 RBDs.
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Project description:Severe acute respiratory symptom coronavirus 2 (SARS-CoV-2) infection occurs via the attachment of the spike (S) protein's receptor binding domain (RBD) to human ACE2 (hACE2). Natural polymorphisms in hACE2, particularly at the interface, may alter RBD-hACE2 interactions, potentially affecting viral infectivity across populations. This study identified the effects of six naturally occurring hACE2 polymorphisms with high allele frequency in the African population (S19P, K26R, M82I, K341R, N546D and D597Q) on the interaction with the S protein RBD of the BA.4/5 Omicron sub-lineage through post-molecular dynamics (MD), inter-protein interaction and dynamic residue network (DRN) analyses. Inter-protein interaction analysis suggested that the K26R variation, with the highest interactions, aligns with reports of enhanced RBD binding and increased SARS-CoV-2 susceptibility. Conversely, S19P, showing the fewest interactions and largest inter-protein distances, agrees with studies indicating it hinders RBD binding. The hACE2 M82I substitution destabilized RBD-hACE2 interactions, reducing contact frequency from 92 (WT) to 27. The K341R hACE2 variant, located distally, had allosteric effects that increased RBD-hACE2 contacts compared to WThACE2. This polymorphism has been linked to enhanced affinity for Alpha, Beta and Delta lineages. DRN analyses revealed that hACE2 polymorphisms may alter the interaction networks, especially in key residues involved in enzyme activity and RBD binding. Notably, S19P may weaken hACE2-RBD interactions, while M82I showed reduced centrality of zinc and chloride-coordinating residues, hinting at impaired communication pathways. Overall, our findings show that hACE2 polymorphisms affect S BA.4/5 RBD stability and modulate spike RBD-hACE2 interactions, potentially influencing SARS-CoV-2 infectivity-key insights for vaccine and therapeutic development.
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