A Computational Dissection of Spike protein of SARS-CoV-2 Omicron Variant

2021 ◽  
Author(s):  
Zaira Rehman ◽  
Massab Umair ◽  
Aamer Ikram ◽  
Muhammad Salman ◽  
Syed Adnan Haider ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Interaction Analysis ◽  
Binding Mechanism ◽  
Wild Type ◽  
Spike Glycoprotein ◽  
Novel Mutations ◽  
Health Authorities ◽  
Rapid Spread ◽  
Novel Interactions ◽  
Computational Dissection

The emergence of SARS-CoV-2 omicron variant in late November, 2021 and its rapid spread to different countries, warns the health authorities to take initiative to work on containing its spread. The omicron SARS-CoV-2 variant is unusual from the other variants of concerns reported earlier as it harbors many novel mutations in its genome particularly with >30 mutations in the spike glycoprotein alone. The current study investigated the variation in binding mechanism which it carries compared to the wild type. The study also explored the interaction profile of spike-omicron with human ACE2 receptor. The structure of omicron spike glycoprotein was determined though homology modeling. The interaction analysis was performed through docking using HADDOCK followed by binding affinity calculation. Finally, the comparison of interactions were performed among spike-ACE2 complex of wild type, delta and omicron variants. The interaction analysis has revealed the involvement of highly charged and polar residues (H505, Arg498, Ser446, Arg493, and Tyr501) in the interactions. The important novel interactions in the spike-ACE2-omicron complex was observed as S494:H34, S496:D38, R498:Y41, Y501:K353, and H505:R393 and R493:D38. Moreover, the binding affinity of spike-ACE2-omicron complex (-17.6Kcal/mol) is much higher than wild type-ACE2 (-13.2Kcal/mol) and delta-ACE2 complex (-13.3Kcal/mol). These results indicate that the involvement of polar and charged residues in the interactions with ACE2 may have an impact on increased transmissibility of omicron variant.

scholarly journals Impact of the N501Y substitution of SARS-CoV-2 Spike on neutralizing monoclonal antibodies targeting diverse epitopes

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Lin Cheng ◽  
Shuo Song ◽  
Bing Zhou ◽  
Xiangyang Ge ◽  
Jiazhen Yu ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Binding Affinity ◽  
Neutralizing Antibodies ◽  
Therapeutic Antibodies ◽  
Wild Type ◽  
Neutralization Activity ◽  
Neutralizing Activity ◽  
Rapid Spread ◽  
Global Concern

AbstractThe emergence and rapid spread of the B.1.1.7 lineage (VOC-202012/01) SARS-CoV-2 variant has aroused global concern. The N501Y substitution is the only mutation in the interface between the RBD of B.1.1.7 and ACE2, raising concerns that its recognition by neutralizing antibodies may be affected. Here, we assessed the neutralizing activity and binding affinity of a panel of 12 monoclonal antibodies against the wild type and N501Y mutant SARS-CoV-2 pseudovirus and RBD protein, respectively. We found that the neutralization activity and binding affinity of most detected antibodies (10 out of 12) were unaffected, although the N501Y substitution decreased the neutralizing and binding activities of CB6 and increased that of BD-23. These findings could be of value in the development of therapeutic antibodies.

Distinct Modulation of Wild-Type and Selective Gene Mutated Vitamin D Receptor by Essential Poly Unsaturated Fatty Acids

2021 ◽  
Vol 21 ◽  
Author(s):  
Hari Balaji ◽  
Selvaraj Ayyamperuma ◽  
Niladri Saha ◽  
Shyam Sundar Pottabathula ◽  
Jubie Selvaraj ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Vitamin D ◽  
Ligand Binding ◽  
Vitamin D Deficiency ◽  
Binding Affinity ◽  
Unsaturated Fatty Acids ◽  
Binding Domain ◽  
Ligand Binding Domain ◽  
Binding Energies ◽  
Wild Type

: Vitamin-D deficiency is a global concern. Gene mutations in the vitamin D receptor’s (VDR) ligand binding domain (LBD) variously alter the ligand binding affinity, heterodimerization with retinoid X receptor (RXR) and inhibit coactivator interactions. These LBD mutations may result in partial or total hormone unresponsiveness. A plethora of evidence report that selective long chain polyunsaturated fatty acids (PUFAs) including eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and arachidonic acid (AA) bind to the ligand-binding domain of VDR and lead to transcriptional activation. We therefore hypothesize that selective PUFAs would modulate the dynamics and kinetics of VDRs, irrespective bioactive of vitamin-D binding. The spatial arrangements of the selected PUFAs in VDR active site were examined by in-silico docking studies. The docking results revealed that PUFAs have fatty acid structure-specific binding affinity towards VDR. The calculated EPA, DHA & AA binding energies (Cdocker energy) were lesser compared to vitamin-D in wild type of VDR (PDB id: 2ZLC). Of note, the DHA has higher binding interactions to the mutated VDR (PDB id: 3VT7) when compared to the standard Vitamin-D. Molecular dynamic simulation was utilized to confirm the stability of potential compound binding of DHA with mutated VDR complex. These findings suggest the unique roles of PUFAs in VDR activation and may offer alternate strategy to circumvent vitamin-D deficiency.

scholarly journals ε2-Phages Are Naturally Bred and Have a Vastly Improved Host Range in Staphylococcus aureus over Wild Type Phages

2021 ◽  
Vol 14 (4) ◽  
pp. 325
Author(s):  
David Sáez Moreno ◽  
Zehra Visram ◽  
Michele Mutti ◽  
Marcela Restrepo-Córdoba ◽  
Susana Hartmann ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Antibiotic Resistance ◽  
Detection Limit ◽  
Host Range ◽  
Alternative Treatment ◽  
Standard Of Care ◽  
Wild Type ◽  
Rapid Spread ◽  
Pharmaceutical Properties ◽  
Human Infections

Due to the rapid spread of antibiotic resistance, and the difficulties of treating biofilm-associated infections, alternative treatments for S. aureus infections are urgently needed. We tested the lytic activity of several wild type phages against a panel of 110 S. aureus strains (MRSA/MSSA) composed to reflect the prevalence of S. aureus clonal complexes in human infections. The plaquing host ranges (PHR) of the wild type phages were in the range of 51% to 60%. We also measured what we called the kinetic host range (KHR), i.e., the percentage of strains for which growth in suspension was suppressed for 24 h. The KHR of the wild type phages ranged from 2% to 49%, substantially lower than the PHRs. To improve the KHR and other key pharmaceutical properties, we bred the phages by mixing and propagating cocktails on a subset of S. aureus strains. These bred phages, which we termed evolution-squared (ε2) phages, have broader KHRs up to 64% and increased virulence compared to the ancestors. The ε2-phages with the broadest KHR have genomes intercrossed from up to three different ancestors. We composed a cocktail of three ε2-phages with an overall KHR of 92% and PHR of 96% on 110 S. aureus strains and called it PM-399. PM-399 has a lower propensity to resistance formation than the standard of care antibiotics vancomycin, rifampicin, or their combination, and no resistance was observed in laboratory settings (detection limit: 1 cell in 1011). In summary, ε2-phages and, in particular PM-399, are promising candidates for an alternative treatment of S. aureus infections.

scholarly journals Rapid spread of the SARS-CoV-2 Delta variant in some French regions, June 2021

2021 ◽  
Vol 26 (28) ◽  
Author(s):  
Samuel Alizon ◽  
Stéphanie Haim-Boukobza ◽  
Vincent Foulongne ◽  
Laura Verdurme ◽  
Sabine Trombert-Paolantoni ◽  
...  
Keyword(s):  
Public Health ◽  
Confidence Interval ◽  
Rapid Growth ◽  
Rt Pcr ◽  
Health Authorities ◽  
Rapid Spread ◽  
Public Health Authorities ◽  
Alpha Variant

We analysed 9,030 variant-specific RT-PCR tests performed on SARS-CoV-2-positive samples collected in France between 31 May and 21 June 2021. This analysis revealed rapid growth of the Delta variant in three of the 13 metropolitan French regions and estimated a +79% (95% confidence interval: 52–110%) transmission advantage compared with the Alpha variant. The next weeks will prove decisive and the magnitude of the estimated transmission advantages of the Delta variant could represent a major challenge for public health authorities.

scholarly journals Screening of Chloroquine, Hydroxychloroquine and Its Derivatives for Their Binding Affinity to Multiple SARS-CoV-2 Protein Drug Targets

2020 ◽  
Author(s):  
Mallikarjuna Nimgampalle ◽  
Vasudharani Devanthan ◽  
Ambrish Saxena
Keyword(s):  
Binding Affinity ◽  
In Silico ◽  
Drug Targets ◽  
Therapeutic Potential ◽  
Viral Proteins ◽  
Protein Drug ◽  
Potential Treatment ◽  
Health Authorities ◽  
Derivatives Of

Recently Chloroquine and its derivative Hydroxychloroquine have garnered enormous interest amongst the clinicians and health authorities’ world over as a potential treatment to contain COVID-19 pandemic. The present research aims at investigating the therapeutic potential of Chloroquine and its potent derivative Hydroxychloroquine against SARS-CoV-2 viral proteins. At the same time we have screened some chemically synthesized derivatives of Chloroquine and compared their binding efficacy with chemically synthesized Chloroquine derivatives through <i>in silico</i>approaches. For the purpose of the study, we have selected some essential viral proteins and enzymes implicated in SARS-CoV-2 replication and multiplication as putative drug targets.<br>

scholarly journals The expression of hACE2 receptor protein and its involvement in SARS-CoV-2 entry, pathogenesis, and its application as potential therapeutic target

Tumor Biology ◽  
2021 ◽  
Vol 43 (1) ◽  
pp. 177-196
Author(s):  
Lobna Al-Zaidan ◽  
Sarra Mestiri ◽  
Afsheen Raza ◽  
Maysaloun Merhi ◽  
Varghese Philipose Inchakalody ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Receptor Binding ◽  
Virus Disease ◽  
Respiratory Illness ◽  
Host Cells ◽  
World Health ◽  
Receptor Protein ◽  
Unknown Etiology ◽  
Spike Glycoprotein ◽  
Binding Interface

Pneumonia cases of unknown etiology in Wuhan, Hubei province, China were reported to the World Health Organization on 31st of December 2019. Later the pathogen was reported to be a novel coronavirus designated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes Corona virus disease 2019 (COVID-19). The disease outspread was followed by WHO declaration of COVID-19 pandemic as a “Public Health Emergency of International Concern”. SARS-CoV-2 is a novel pathogenic beta coronavirus that infects humans causing severe respiratory illness. However, multifarious factors can contribute to the susceptibility to COVID-19 related morbidity and mortality such as age, gender, and underlying comorbidities. Infection initiates when viral particles bind to the host cell surface receptors where SARS-CoV-2 spike glycoprotein subunit 1 binds to the Angiotensin Converting Enzyme 2 (ACE2). It is of importance to mention that SARS-CoV and SARS-CoV-2 viruses’ mediate entry into the host cells via ACE2 receptor which might be correlated with the structural similarity of spike glycoprotein subunit 1 of both SARS viruses. However, the structural binding differs, whereas ACE2 receptor binding affinity with SARS-CoV-2 is 4 folds higher than that with SARS-CoV. Moreover, amino acids sequence divergence between the two S glycoproteins might be responsible for differential modulations of the specific immune response to both viruses. Identification of different aspects such as binding affinity, differential antigenic profiles of S-glycoproteins, and ACE2 mutations might influence the investigation of potential therapeutic strategies targeting SARS-CoV-2/ACE2 binding interface. In this review, we aim to elaborate on the expression of hACE2 receptor protein and its binding with SARS-CoV-2 S1 subunit, the possible immunogenic sequences of spike protein, effect of ACE 2 polymorphism on viral binding, and infectivity/susceptibility to disease. Furthermore, targeting of hACE2 receptor binding with SARS-CoV-2 S1 subunit via various mechanisms will be discussed to understand its role in therapeutics.

scholarly journals Identification of novel mutations contributing to azole tolerance of Aspergillus fumigatus through in vitro exposure to tebuconazole

2020 ◽  
Author(s):  
Takahito Toyotome ◽  
Kenji Onishi ◽  
Mio Sato ◽  
Yoko Kusuya ◽  
Daisuke Hagiwara ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Parental Strain ◽  
Resistance Mechanisms ◽  
Wild Type ◽  
Genome Sequences ◽  
Novel Mutations ◽  
Mutant Selection ◽  
Synonymous Mutations ◽  
Azole Tolerance

AbstractAzole resistance of Aspergillus fumigatus is a global problem. The major resistant mechanism is a cyp51A alteration such as mutation(s) in the gene and the acquisition of a tandem repeat in the promoter. Although other azole tolerances and resistant mechanisms such as hmg1 mutation are known, few reports describe studies elucidating non-cyp51A resistance mechanisms. This study explored genes contributing to azole tolerance in A. fumigatus by in vitro mutant selection with tebuconazole, an azole fungicide. After three-round selection, we obtained four isolates with low susceptibility to tebuconazole. These isolates also showed low susceptibility to itraconazole and voriconazole. Comparison of the genome sequences of the obtained isolates and the parental strain revealed a non-synonymous mutation in MfsD (Afu1g11820, R337L mutation) in all isolates. Furthermore, non-synonymous mutations in AgcA (Afu7g05220, E535Stop mutation), UbcD (Afu3g06030, T98K mutation), AbcJ (Afu3g12220, G297E mutation), and RttA (Afu7g04740, A83T mutation), a protein responsible for tebuconazole tolerance, were found in at least one isolate. Clarification by constructing the MfsD R337L mutant suggests that the mutation contributes to azole tolerance. Disruption of the agcA gene and reconstruction of the A83T point mutation in RttA led to decreased susceptibility to azoles. The reversion of T98K mutation to wild type in UbcD led to the level of azole susceptibility comparable to the parental strain. These results suggest that these mutations contribute to lowered susceptibility to medical azoles and to agricultural azole fungicides.

scholarly journals Probing allosteric coupling in a constitutively open mutant of the ion channel KcsA using solid-state NMR

2020 ◽  
Vol 117 (13) ◽  
pp. 7171-7175
Author(s):  
Zhiyu Sun ◽  
Yunyao Xu ◽  
Dongyu Zhang ◽  
Ann E. McDermott
Keyword(s):  
Solid State ◽  
Binding Affinity ◽  
Solid State Nmr ◽  
Selectivity Filter ◽  
Wild Type ◽  
Proton Binding ◽  
Allosteric Coupling ◽  
Neutral Ph ◽  
Potassium Channel Kcsa ◽  
Potassium Binding

Transmembrane allosteric coupling is a feature of many critical biological signaling events. Here we test whether transmembrane allosteric coupling controls the potassium binding affinity of the prototypical potassium channel KcsA in the context of C-type inactivation. Activation of KcsA is initiated by proton binding to the pH gate upon an intracellular drop in pH. Numerous studies have suggested that this proton binding also prompts a conformational switch, leading to a loss of affinity for potassium ions at the selectivity filter and therefore to channel inactivation. We tested this mechanism for inactivation using a KcsA mutant (H25R/E118A) that exhibits an open pH gate across a broad range of pH values. We present solid-state NMR measurements of this open mutant at neutral pH to probe the affinity for potassium at the selectivity filter. The potassium binding affinity in the selectivity filter of this mutant, 81 mM, is about four orders of magnitude weaker than that of wild-type KcsA at neutral pH and is comparable to the value for wild-type KcsA at low pH (pH ≈ 3.5). This result strongly supports our assertion that the open pH gate allosterically affects the potassium binding affinity of the selectivity filter. In this mutant, the protonation state of a glutamate residue (E120) in the pH sensor is sensitive to potassium binding, suggesting that this mutant also has flexibility in the activation gate and is subject to transmembrane allostery.

An innovative method for the selection of inhibitors of the viral spike-glycoprotein of the SARS-CoV

2020 ◽  
pp. 2050043
Author(s):  
T. V. Koshlan ◽  
K. G. Kulikov
Keyword(s):  
Active Center ◽  
Protein Interactions ◽  
Software Package ◽  
Wild Type ◽  
Spike Glycoprotein ◽  
Innovative Method ◽  
Detailed Method ◽  
Step Algorithm ◽  
Natural Peptides ◽  
Selection Of

This paper has developed and described a detailed method for selecting inhibitors based on modified natural peptides for the SARS-CoV BJ01 spike-glycoprotein. The selection of inhibitors is carried out by increasing the affinity of the peptide to the active center of the protein. This paper also provides a step-by-step algorithm for analyzing the affinity of protein interactions and presents an analysis of energy interactions between the active center of a protein and the wild-type peptide interacting with it, taking into account modifications of the latter. A description of the software package that implements the presented algorithm is given on the website https://binomlabs.com/covid19 .

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