SARS-CoV-2 Omicron Subvariants Do Not Differ Much in Binding Affinity to Human ACE2: A Molecular Dynamics Study

The Journal of Physical Chemistry B, Journal Year: 2024, Volume and Issue: 128(14), P. 3340 - 3349

Published: April 2, 2024

The emergence of the variant concern Omicron (B.1.1.529) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exacerbates COVID-19 pandemic due to its high contagious ability. Studies have shown that binds human ACE2 more strongly than wild type. prevalence in new cases promotes novel lineages with improved receptor binding affinity and immune evasion. To shed light on this open problem, work, we investigated free energy domain BA.2, BA.2.3.20, BA.3, BA4/BA5, BA.2.75, BA.2.75.2, BA.4.6, XBB.1, XBB.1.5, BJ.1, BN.1, BQ.1.1, CH.1.1 using all-atom molecular dynamics simulation mechanics Poisson–Boltzmann surface area method. results show these increased compared BA.1 lineage, BA.2.75 BA.2.75.2 subvariants bind others. However, general, affinities do not differ significantly from each other. electrostatic force dominates over van der Waals interaction between cells. Based our results, argue viral evolution does further improve SARS-CoV-2 for but may increase

Language: Английский

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Development of a Recombinant Omicron BA.1 Subunit Vaccine Candidate in Pichia pastoris

Microbial Biotechnology, Journal Year: 2025, Volume and Issue: 18(1)

Published: Jan. 1, 2025

ABSTRACT Low‐cost and safe vaccines are needed to fill the vaccine inequity gap for future pandemics. Pichia pastoris is an ideal expression system recombinant protein production due its cost‐effective easy‐to‐scale‐up process. Here, we developed a next‐generation SARS‐CoV2 Omicron BA.1‐based candidate expressed in P. . The receptor binding domain of BA.1 spike (RBD‐Omicron) was produced at 0.35 g/L supernatant. With 60% recovery after two‐step purification, RBD‐Omicron showed 99% purity. After vitro characterisation purified via chromatography, mass spectrometry, calorimetry surface plasmon resonance‐based methods, it injected into mice immunization studies. Three different doses Alum CpG adjuvanted were investigated 10 μg gave highest antigenicity. two vaccination, IgG titers serum reached more than 6 These antibodies also recognized earlier (Delta Plus: B.1.617.2) later (Eris: EG.5, Pirola: BA.2.86) variants. long‐term immunological response measured by analyzing antibody T‐cell splenocytes 60 weeks. Interestingly, Th1 significantly high even year. subvariants dominantly circulating world, so sub‐lineage‐based can be used RBD‐Omicron‐based this study suitable technology transfer transition clinic.

Language: Английский

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Molecular Determinants for the Binding of the Highly Infectious SARS-CoV-2 Omicron (BA.1) Variant to the Human ACE2 Receptor

Physchem, Journal Year: 2025, Volume and Issue: 5(1), P. 8 - 8

Published: Feb. 20, 2025

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, continually undergoes mutation, leading to variants with altered pathogenicity and transmissibility. The Omicron variant (B.1.1.529), first identified in South Africa 2021, has become dominant strain worldwide. It harbors approximately 50 mutations compared original strain, 15 located receptor-binding domain (RBD) spike protein that facilitates viral entry via binding human angiotensin-converting enzyme (ACE2) receptor. How do these mutated residues modulate intermolecular interactions affinity between RBD ACE2? This is a question great theoretical importance practical implication. In this study, we employed quantum chemical calculations at B2PLYP-D3/def2-TZVP level theory investigate molecular determinants governing Omicron’s ACE2 interaction. Comparative analysis wild-type RBD–ACE2 interfaces revealed including S477N, Q493R, Q498R, N501Y enhance through formation bifurcated hydrogen bonds, π–π stacking, cation–π interactions. These favorable counterbalance such destabilizing as K417N, G446S, G496S, Y505H, which disrupt salt bridges bonds. Additionally, allosteric effects improve contributions non-mutated (notably A475, Y453, F486) structural realignment novel bonding S19, an overall increase electrostatic π-system interaction energy. conclusion, our findings provide mechanistic basis for increased infectivity offer valuable insights development targeted antiviral therapies. Moreover, from methodological perspective, directly calculated mutation-induced energy changes residue using advanced methods rather than relying on indirect decomposition schemes typical dynamics-based free analyses. strong correlation differences experimental deep mutational scanning (DMS) data underscores robustness framework predicting affinity. demonstrates potential predictive tools studying protein–protein guiding rational therapeutic design.

Language: Английский

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Biophysics of SARS-CoV-2 spike protein’s receptor-binding domain interaction with ACE2 and neutralizing antibodies: from computation to functional insights

Biophysical Reviews, Journal Year: 2025, Volume and Issue: unknown

Published: March 8, 2025

Language: Английский

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Electrostatic Interactions Are the Primary Determinant of the Binding Affinity of SARS-CoV-2 Spike RBD to ACE2: A Computational Case Study of Omicron Variants

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(23), P. 14796 - 14796

Published: Nov. 26, 2022

To explore the mechanistic origin that determines binding affinity of SARS-CoV-2 spike receptor domain (RBD) to human angiotensin converting enzyme 2 (ACE2), we constructed homology models RBD-ACE2 complexes four Omicron subvariants (BA.1, BA.2, BA.3 and BA.4/5), compared them with wild type complex (RBDWT-ACE2) in terms various structural dynamic properties by molecular dynamics (MD) simulations free energy (BFE) calculations. The results MD suggest RBDs all (RBDOMIs) feature increased global fluctuations when RBDWT. Detailed comparison BFE components reveals enhanced electrostatic attractive interactions are main determinant higher ACE2-binding RBDOMIs than RBDWT, while weakened determine RBD BA.4/5 subvariant (RBDBA.4/5) lowest among subvariants. per-residue decompositions hydrogen bond (HB) networks analyses indicate mainly through gain/loss positively/negatively charged residues, formation or destruction interfacial HBs salt bridges can also largely affect RBD. It is worth pointing out since Q493R plays most important positive contribution enhancing affinity, absence this mutation RBDBA.4/5 a significantly weaker ACE2 other Our provide insight into role determining ACE2.

Language: Английский

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Is BF.7 more infectious than other Omicron subtypes: Insights from structural and simulation studies of BF.7 spike RBD variant

International Journal of Biological Macromolecules, Journal Year: 2023, Volume and Issue: 238, P. 124154 - 124154

Published: March 24, 2023

Language: Английский

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When the Dust Has Settled: Calculation of Binding Affinities from First Principles for SARS-CoV-2 Variants with Quantitative Accuracy

Journal of Chemical Theory and Computation, Journal Year: 2022, Volume and Issue: 18(10), P. 5890 - 5900

Published: Sept. 15, 2022

Accurate determination of binding free energy is pivotal for the study many biological processes and has been applied in a number theoretical investigations to compare affinity severe acute respiratory syndrome coronavirus 2 variants toward host cell. Diversity these challenges development effective general therapies, their transmissibility relying either on an increased dedicated human receptor, angiotensin-converting enzyme (ACE2), or escaping immune response. Now that robust structural data are available, we have determined with utmost accuracy standard receptor-binding domain most widespread variants, namely, Alpha, Beta, Delta, Omicron BA.2, as well wild type (WT) complex ACE2 antibodies, S2E12 H11-D4, using rigorous framework combines molecular dynamics potential-of-mean-force calculations. Our results show appropriate starting structure crucial ensure reproduction affinity, allowing be compared. They also emphasize necessity apply relevant methodology, bereft any shortcut, account all contributions energy. estimates affinities support view while Alpha Beta lean cell, Delta BA.2 choose escape. Moreover, antibody, already known active against WT (Starr et al., 2021; Mlcochova 2021), proved equally variant. In stark contrast, H11-D4 retains low compared latter. Assuming information, methodology employed herein successfully addresses challenging protein-protein problem context disease 2019 offering promising perspectives predictive studies ever-emerging variants.

Language: Английский

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Molecular insights and optimization strategies for the competitive binding of engineered ACE2 proteins: a multiple replica molecular dynamics study

Physical Chemistry Chemical Physics, Journal Year: 2023, Volume and Issue: 25(41), P. 28479 - 28496

Published: Jan. 1, 2023

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) continues to spread globally, and rapid viral evolution the emergence of new variants pose challenges control. During infection, spike protein SARS-CoV-2 interacts with human ACE2 via its receptor binding domain (RBD), it is known that engineered forms can compete wild-type (WT) for inhibit infection. Here, we conducted multiple replica molecular dynamics (MRMD) simulations study mechanisms 3N39 3N94 provide directions optimization. Our findings reveal notably more efficacious in systems show weaker WT (i.e., BA.1 RBD), but also faces immune escape as virus evolves. Moreover, modifying residue types near interface, alters electrostatic potential distribution reconfigures hydrogen bonding network, which results modified RBD. However, this structural rearrangement does not occur all RBD variants. In addition, identified potentially engineerable beneficial residues detrimental both Functional conservation thus enable optimization these improve competitiveness ACE2, therefore provides additional prevention. Finally, conclude have implications understanding responsible help us develop proteins superior performance.

Language: Английский

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Unraveling the binding mechanisms of SARS-CoV-2 variants through molecular simulations

Heliyon, Journal Year: 2024, Volume and Issue: 10(5), P. e27193 - e27193

Published: Feb. 29, 2024

The emergence of SARS-CoV-2 variants like Delta (AY.29) and Omicron (EG.5) poses continued challenges for vaccines therapeutics. Mutations in the viral spike protein are key altering infectivity immune evasion. This study uses computational modeling to investigate molecular binding mechanisms between ACE2 host receptor. Using MARTNI force field, coarse-grained dynamics (CGMD) simulations nudged elastic band (NEB) calculations explore spike-ACE2 interactions wild type, variant, variant. reveal has strongest affinity at -128.35 ± 10.91 kcal/mol, followed by type. Key mutations Omicron, Q493R Q498R, optimize electrostatic contacts, enhancing interactions. wild-type highest transition state energy barrier 17.87 while lowest 9.21 kcal/mol. Despite slightly higher dual barriers, Omicron's increased lowers its overall rapidly bind ACE2. These findings provide residue-level insights into mutation effects on infectivity. elucidates underlying kinetics, aiding development therapies targeting emerging strains.

Language: Английский

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A computationally designed ACE2 decoy has broad efficacy against SARS-CoV-2 omicron variants and related viruses in vitro and in vivo

Communications Biology, Journal Year: 2023, Volume and Issue: 6(1)

Published: May 12, 2023

Abstract SARS-CoV-2, especially B.1.1.529/omicron and its sublineages, continues to mutate evade monoclonal antibodies elicited by vaccination. Affinity-enhanced soluble ACE2 (sACE2) is an alternative strategy that works binding the SARS-CoV-2 S protein, acting as a ‘decoy’ block interaction between human ACE2. Using computational design strategy, we designed affinity-enhanced decoy, FLIF , exhibited tight delta omicron variants. Our computationally calculated absolute free energies (ABFE) sACE2:SARS-CoV-2 proteins their variants showed excellent agreement experiments. displayed robust therapeutic utility against broad range of sarbecoviruses, neutralized BA.5 in vitro vivo. Furthermore, directly compared vivo efficacy wild-type (non-affinity enhanced ACE2) . A few sACE2 decoys have shown be effective early circulating such Wuhan data suggest moving forward, like may required combat evolving The approach described herein emphasizes how methods become sufficiently accurate for therapeutics viral protein targets. remain highly at neutralizing subvariants.

Language: Английский

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