E484K mutation in SARS-CoV-2 RBD enhances binding affinity with hACE2 but reduces interactions with neutralizing antibodies and nanobodies: Binding free energy calculation studies

Wang, Wei Bu; Liang, Yu; Jin, Yu; Zhang, Jing; Su, Ji Guo; Li, Qi Ming

doi:10.1016/j.jmgm.2021.108035

Cited by 54 publications

(62 citation statements)

References 49 publications

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“…K417N can boost RBD surface expression and resistance to neutralizing monoclonal antibodies in a mild way, similar to the Beta variant (20H, B.1.351). 44 A few substituted residues in the Omicron RBD‐hACE2 complex reduce the binding interactions between RBD and hACE2, whereas others increase it. Omicron RBDs with the K417N mutation were also found in Beta, Gamma, and even some Delta lineage RBDs.…”

Section: Genetic Mutations In Omicronmentioning

confidence: 99%

Emerging evidence on Omicron (B.1.1.529) SARS‐CoV‐2 variant

Sharma

Rai

Gautam

et al. 2022

Journal of Medical Virology

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COVID's Omicron variant has sparked a slew of concerns across the globe. This review aims to provide a brief overview of what we know about the Omicron variant right now. The new variant has been discovered in 149 countries across all six World Health Organization (WHO) regions since its discovery in South Africa on November 24, 2021 and became the dominant variant in the country in less than 3 weeks. The WHO has warned that the B.1.1.529 variant is spreading at an unprecedented rate, and has urged countries to prepare for the worst. Over the course of this time, researchers from Africa and around the world have uncovered a wealth of information about the virus's epidemiology and biological properties. Case numbers are increasing exponentially in hard‐hit areas such as South Africa, United Kingdom, and USA (overtaking the delta variant), implying that the variant is highly transmissible. Initial research has provided some insights into the efficacy of vaccines against the Omicron variant and whether it produces major illness, however, much remains unknown, and additional work is needed to investigate what the initial reports represent in real‐world situations.

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Section: Genetic Mutations In Omicronmentioning

confidence: 99%

Emerging evidence on Omicron (B.1.1.529) SARS‐CoV‐2 variant

Sharma

Rai

Gautam

et al. 2022

Journal of Medical Virology

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“…G GB and G SA are the electrostatic and non-electrostatic contributions to the solvation free energy, respectively. G GB was computed using the Poisson–Boltzmann (PB) equation, and G SA was estimated from the solvent-accessible surface area (SASA) equation estimated by using a water probe radius of 1.4 Å. T and S are the temperature and the total solute entropy, respectively; γ is a coefficient related to the surface tension of the solvent [ 55 , 56 ]. A constant γ = 0.0072 kcal/mol/Å2 was used with Amber PB polar solvation energies.…”

Section: Methodsmentioning

confidence: 99%

Impact of the R292K Mutation on Influenza A (H7N9) Virus Resistance towards Peramivir: A Molecular Dynamics Perspective

2022

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In March 2013, a novel avian influenza A (H7N9) virus emerged in China. By March 2021, it had infected more than 1500 people, raising concerns regarding its epidemic potential. Similar to the highly pathogenic H5N1 virus, the H7N9 virus causes severe pneumonia and acute respiratory distress syndrome in most patients. Moreover, genetic analysis showed that this avian H7N9 virus carries human adaptation markers in the hemagglutinin and polymerase basic 2 (PB2) genes associated with cross-species transmissibility. Clinical studies showed that a single mutation, neuraminidase (NA) R292K (N2 numbering), induces resistance to peramivir in the highly pathogenic H7N9 influenza A viruses. Therefore, to evaluate the risk for human public health and understand the possible source of drug resistance, we assessed the impact of the NA-R292K mutation on avian H7N9 virus resistance towards peramivir using various molecular dynamics approaches. We observed that the single point mutation led to a distorted peramivir orientation in the enzyme active site which, in turn, perturbed the inhibitor’s binding. The R292K mutation induced a decrease in the interaction among neighboring amino acid residues when compared to its wild-type counterpart, as shown by the high degree of fluctuations in the radius of gyration. MM/GBSA calculations revealed that the mutation caused a decrease in the drug binding affinity by 17.28 kcal/mol when compared to the that for the wild-type enzyme. The mutation caused a distortion of hydrogen bond-mediated interactions with peramivir and increased the accessibility of water molecules around the K292 mutated residue.

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“…These substitutions can achieve typical consequences, such as the alteration of viral entry efficiency, the increase of immune evasive ability, or both. For example, the mutation E484K in the SARS-CoV-2 receptor binding domain (RBD) enhances binding affinity with hACE2 and increases the viral infectivity, but reduces the binding affinity of many neutralizing antibodies 33 , 34 , 35 , 36 . Notably, the Omicron harbors over 30 amino acid substitutions in the Spike, 15 of which are in the RBD.…”

Section: Why Do Sars-cov-2 Variants Constantly Emerge?mentioning

confidence: 99%