Higher infectivity of the SARS‐CoV‐2 new variants is associated with K417N/T, E484K, and N501Y mutants: An insight from structural data

Khan, Abbas; Zia, Tauqir; Suleman, Muhammad; Khan, Taimoor; Ali, Syed Shujait; Abbasi, Aamir Ali; Mohammad, Anwar; Wei, Dong

doi:10.1002/jcp.30367

Cited by 321 publications

(476 citation statements)

References 51 publications

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“…In this regard, in silico techniques such as MD simulations were utilized to study the said mutations role in PZase resistance to PZA. These methods are widely used to understand the mechanism of resistance and any binding perturbation caused by mutations ( Khan et al, 2020c , e , 2021a , b ). It unveils conformational changes of proteins caused by any intrinsic mutations or ligand binding.…”

Section: Discussionmentioning

confidence: 99%

Insights Into Mutations Induced Conformational Changes and Rearrangement of Fe2+ Ion in pncA Gene of Mycobacterium tuberculosis to Decipher the Mechanism of Resistance to Pyrazinamide

Nangraj

Khan

Umbreen

et al. 2021

Front. Mol. Biosci.

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Pyrazinamide (PZA) is the first-line drug commonly used in treating Mycobacterium tuberculosis (Mtb) infections and reduces treatment time by 33%. This prodrug is activated and converted to an active form, Pyrazinoic acid (POA), by Pyrazinamidase (PZase) enzyme. Mtb resistance to PZA is the outcome of mutations frequently reported in pncA, rpsA, and panD genes. Among the mentioned genes, pncA mutations contribute to 72–99% of the total resistance to PZA. Thus, considering the vital importance of this gene in PZA resistance, its frequent mutations (D49N, Y64S, W68G, and F94A) were investigated through in-depth computational techniques to put conclusions that might be useful for new scaffolds design or structure optimization to improve the efficacy of the available drugs. Mutants and wild type PZase were used in extensive and long-run molecular dynamics simulations in triplicate to disclose the resistance mechanism induced by the above-mentioned point mutations. Our analysis suggests that these mutations alter the internal dynamics of PZase and hinder the correct orientation of PZA to the enzyme. Consequently, the PZA has a low binding energy score with the mutants compared with the wild type PZase. These mutations were also reported to affect the binding of Fe2+ ion and its coordinated residues. Conformational dynamics also revealed that β-strand two is flipped, which is significant in Fe2+ binding. MM-GBSA analysis confirmed that these mutations significantly decreased the binding of PZA. In conclusion, these mutations cause conformation alterations and deformities that lead to PZA resistance.

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Section: Discussionmentioning

confidence: 99%

Insights Into Mutations Induced Conformational Changes and Rearrangement of Fe2+ Ion in pncA Gene of Mycobacterium tuberculosis to Decipher the Mechanism of Resistance to Pyrazinamide

Nangraj

Khan

Umbreen

et al. 2021

Front. Mol. Biosci.

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“…Recombinant vaccines comprising the Spike RBD induced potent antibody response in immunized animal models such as mouse, rabbits and primates [13]. On the other hand, mutations in the RBD can improve viral affinity to ACE2 and the evasion from neutralization antibodies [8,[14][15][16]. A recently published clinical study [17] has shown also a decreased vaccine efficacy against the lineage B.1.351 (carrying Spike mutations E484K and N501Y), testifying the need to track and monitor all SARS-CoV-2 mutations, with a particular accent on those affecting the Spike RBD.…”

Section: Introductionmentioning

confidence: 99%

Preliminary report on SARS-CoV-2 Spike mutation T478K

Giacomo

Mercatelli

Рахимов

et al. 2021

Preprint

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Several SARS-CoV-2 variants have emerged, posing a renewed threat to COVID-19 containment and to vaccine and drug efficacy. In this study, we analyzed more than 820,000 SARS-CoV-2 genomic sequences deposited up to March 26, 2021 and identified a novel T478K mutation located on the SARS-CoV-2 Spike protein. The mutation is structurally located in the region of interaction with human receptor ACE2 and was detected in 4,214 distinct cases. We show that T478K has appeared and risen in frequency since January 2021, predominantly in Mexico and North America, but we could also detect it in several European countries.

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“…This explains to a certain extent the phenomenon that the well-known N501 mutation will lead to stronger affinity. 44 …”

Section: Resultsmentioning

confidence: 99%

Anchor-Locker Binding Mechanism of the Coronavirus Spike Protein to Human ACE2: Insights from Computational Analysis

Cong

Yan

et al. 2021

J. Chem. Inf. Model.

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COVID-19 has emerged as the most serious international pandemic in early 2020 and the lack of comprehensive knowledge in the recognition and transmission mechanisms of this virus hinders the development of suitable therapeutic strategies. The specific recognition during the binding of the spike glycoprotein (S protein) of coronavirus to the angiotensin-converting enzyme 2 (ACE2) in the host cell is widely considered the first step of infection. However, detailed insights on the underlying mechanism of dynamic recognition and binding of these two proteins remain unknown. In this work, molecular dynamics simulation and binding free energy calculation were carried out to systematically compare and analyze the receptor-binding domain (RBD) of six coronavirus’ S proteins. We found that affinity and stability of the RBD from SARS-CoV-2 under the binding state with ACE2 are stronger than those of other coronaviruses. The solvent-accessible surface area (SASA) and binding free energy of different RBD subunits indicate an “anchor-locker” recognition mechanism involved in the binding of the S protein to ACE2. Loop 2 (Y473-F490) acts as an anchor for ACE2 recognition, and Loop 3 (G496-V503) locks ACE2 at the other nonanchoring end. Then, the charged or long-chain residues in the β-sheet 1 (N450-F456) region reinforce this binding. The proposed binding mechanism was supported by umbrella sampling simulation of the dissociation process. The current computational study provides important theoretical insights for the development of new vaccines against SARS-CoV-2.

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Higher infectivity of the SARS‐CoV‐2 new variants is associated with K417N/T, E484K, and N501Y mutants: An insight from structural data

Cited by 321 publications

References 51 publications

Insights Into Mutations Induced Conformational Changes and Rearrangement of Fe2+ Ion in pncA Gene of Mycobacterium tuberculosis to Decipher the Mechanism of Resistance to Pyrazinamide

Insights Into Mutations Induced Conformational Changes and Rearrangement of Fe2+ Ion in pncA Gene of Mycobacterium tuberculosis to Decipher the Mechanism of Resistance to Pyrazinamide

Preliminary report on SARS-CoV-2 Spike mutation T478K

Anchor-Locker Binding Mechanism of the Coronavirus Spike Protein to Human ACE2: Insights from Computational Analysis

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