scholarly journals Atomistic Simulations and In Silico Mutational Profiling of Protein Stability and Binding in the SARS-CoV-2 Spike Protein Complexes with Nanobodies: Molecular Determinants of Mutational Escape Mechanisms

ACS Omega ◽  
2021 ◽  
Author(s):  
Gennady M. Verkhivker ◽  
Steve Agajanian ◽  
Deniz Yasar Oztas ◽  
Grace Gupta
Keyword(s):  
Protein Stability ◽  
In Silico ◽  
Protein Complexes ◽  
Spike Protein ◽  
Atomistic Simulations ◽  
Mutational Profiling ◽  
Molecular Determinants

scholarly journals Dissecting Molecular Determinants of Mutational Escape Mechanisms in the SARS-CoV-2 Spike Protein Complexes with Nanobodies: Atomistic Simulations and Ensemble-Based Deep Mutational Scanning of Protein Stability and Binding Interactions

2021 ◽  
Author(s):  
Gennady Verkhivker ◽  
Steve Agajanian ◽  
Deniz Yasar Oztas ◽  
Grace Gupta
Keyword(s):  
Molecular Mechanisms ◽  
Protein Complexes ◽  
Conformational Dynamics ◽  
Spike Protein ◽  
Atomistic Simulations ◽  
Binding Interactions ◽  
Mutational Profiling ◽  
Neutralizing Capacity ◽  
The Stability ◽  
Protein Response

Structural and biochemical studies have recently revealed a range of rationally engineered nanobodies with efficient neutralizing capacity against SARS-CoV-2 virus and resilience against mutational escape. In this work, we combined atomistic simulations and conformational dynamics analysis with the ensemble-based mutational profiling of binding interactions for a diverse panel of SARS-CoV-2 spike complexes with nanobodies. Using this computational toolkit, we identified dynamic signatures and binding affinity fingerprints for the SARS-CoV-2 spike protein complexes with nanobodies Nb6 and Nb20, VHH E, a pair combination VHH E+U, a biparatopic nanobody VHH VE, and a combination of CC12.3 antibody and VHH V/W nanobodies. Through ensemble-based deep mutational profiling of stability and binding affinities, we identify critical hotspots and characterize molecular mechanisms of SARS-CoV-2 spike protein binding with single ultra-potent nanobodies, nanobody cocktails and biparatopic nanobodies. By quantifying dynamic and energetic determinants of the SARS-CoV-2 S binding with nanobodies, we also examine the effects of circulating variants and escaping mutations. We found that mutational escape mechanisms may be controlled through structurally and energetically adaptable binding hotspots located in the host receptor-accessible binding epitope that are dynamically coupled to the stability centers in the distant epitope targeted by VHH U/V/W nanobodies. The results of this study suggested a mechanism in which through cooperative dynamic changes, nanobody combinations and biparatopic nanobody can modulate the global protein response and induce the increased resilience to common escape mutants.

scholarly journals Atomistic Simulations and Deep Mutational Scanning of Protein Stability and Binding Interactions in the SARS-CoV-2 Spike Protein Complexes with Nanobodies: Molecular Determinants of Mutational Escape Mechanisms

2021 ◽  
Author(s):  
Gennady Verkhivker ◽  
Steve Agajanian ◽  
Deniz Yasar Oztas ◽  
Grace Gupta
Keyword(s):  
Molecular Mechanisms ◽  
Protein Complexes ◽  
Conformational Dynamics ◽  
Spike Protein ◽  
Atomistic Simulations ◽  
Binding Interactions ◽  
Mutational Profiling ◽  
Neutralizing Capacity ◽  
The Stability ◽  
Protein Response

Structural and biochemical studies have recently revealed a range of rationally engineered nanobodies with efficient neutralizing capacity against SARS-CoV-2 virus and resilience against mutational escape. In this work, we combined atomistic simulations and conformational dynamics analysis with the ensemble-based mutational profiling of binding interactions for a diverse panel of SARS-CoV-2 spike complexes with nanobodies. Using this computational toolkit we identified dynamic signatures and binding affinity fingerprints for the SARS-CoV-2 spike protein complexes with nanobodies Nb6 and Nb20, VHH E, a pair combination VHH E+U, a biparatopic nanobody VHH VE, and a combination of CC12.3 antibody and VHH V/W nanobodies. Through ensemble-based deep mutational profiling of stability and binding affinities, we identify critical hotspots and characterize molecular mechanisms of SARS-CoV-2 spike protein binding with single ultra-potent nanobodies, nanobody cocktails and biparatopic nanobodies. By quantifying dynamic and energetic determinants of the SARS-CoV-2 S binding with nanobodies, we also examine the effects of circulating variants and escaping mutations. We found that mutational escape mechanisms may be controlled through structurally and energetically adaptable binding hotspots located in the host receptor-accessible binding epitope that are dynamically coupled to the stability centers in the distant epitope targeted by VHH U/V/W nanobodies. The results of this study suggested a mechanism in which through cooperative dynamic changes, nanobody combinations and biparatopic nanobody can modulate the global protein response and induce the increased resilience to common escape mutants.

scholarly journals Elucidation of the interactions between SARS-CoV-2 Spike protein and wild and mutant types of IFITM proteins by in silico methods

2021 ◽  
Author(s):  
Nazli Irmak Giritlioglu ◽  
Gizem Koprululu Kucuk
Keyword(s):  
Molecular Docking ◽  
Amino Acid ◽  
Binding Energy ◽  
Hydrogen Bonds ◽  
In Silico ◽  
Protein Complexes ◽  
Protein Product ◽  
Binding Energies ◽  
Spike Protein ◽  
Web Based

COVID-19 is a viral disease that has been a threat to the whole world since 2019. Although effective vaccines against the disease have been developed, there are still points to be clarified about the mechanism of SARS-CoV-2, which is the causative agent of COVID-19. In this study, we determined the binding energies and the bond types of complexes formed by open (6VYB) and closed (6VXX) forms of the Spike protein of SARS-CoV-2 and wild and mutant forms of IFITM1, IFITM2, and IFITM3 proteins using the molecular docking approach. First, all missense SNPs were found in the NCBI Single Nucleotide Polymorphism database (dbSNP) for IFITM1, IFITM2, and IFITM3 and analyzed with SIFT, PROVEAN, PolyPhen-2, SNAP2, Mutation Assessor, and PANTHER cSNP web-based tools to determine their pathogenicity. When at least four of these analysis tools showed that the SNP had a pathogenic effect on the protein product, this SNP was saved for further analysis. Delta delta G (DDG) and protein stability analysis for amino acid changes were performed in the web-based tools I-Mutant, MUpro, and SAAFEC-SEQ. The structural effect of amino acid change on the protein product was made using the HOPE web-based tool. HawkDock server was used for molecular docking and Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) analysis and binding energies of all complexes were calculated. BIOVIA Discovery Studio program was utilized to visualize the complexes. Hydrogen bonds, salt bridges, and non-bonded contacts between Spike and IFITM protein chains in the complexes were detected with the PDBsum web-based tool. The best binding energy among the 6VYB-IFITM wild protein complexes belong to 6VYB-IFITM1 (-46.16 kcal/mol). Likewise, among the 6VXX-IFITM wild protein complexes, the most negative binding energy belongs to 6VXX-IFITM1 (-52.42 kcal/mol). An interesting result found in the study is the presence of hydrogen bonds between the cytoplasmic domain of the IFITM1 wild protein and the S2 domain of 6VYB. Among the Spike-IFITM mutant protein complexes, the best binding energy belongs to the 6VXX-IFITM2 N63S complex (-50.77 kcal/mol) and the worst binding energy belongs to the 6VXX-IFITM3 S50T complex (4.86 kcal/mol). The study suggests that IFITM1 protein may act as a receptor for SARS-CoV-2 Spike protein. Assays must be advanced from in silico to in vitro for the determination of the receptor-ligand interactions between IFITM proteins and SARS-CoV-2.

scholarly journals Phytocompounds of Rheum emodi, Thymus serpyllum, and Artemisia annua Inhibit Spike Protein of SARS-CoV-2 Binding to ACE2 Receptor: In Silico Approach

2021 ◽  
Author(s):  
Rajan Rolta ◽  
Deeksha Salaria ◽  
PremPrakash Sharma ◽  
Bhanu Sharma ◽  
Vikas Kumar ◽  
...  
Keyword(s):  
In Silico ◽  
Artemisia Annua ◽  
Spike Protein ◽  
Thymus Serpyllum

scholarly journals Andrographis paniculata (Burm. F.) Wall. Ex Nees, Andrographolide, and Andrographolide Analogues as SARS-CoV-2 Antivirals? A Rapid Review

2021 ◽  
Vol 16 (5) ◽  
pp. 1934578X2110166
Author(s):  
Xin Yi Lim ◽  
Janice Sue Wen Chan ◽  
Terence Yew Chin Tan ◽  
Bee Ping Teh ◽  
Mohd Ridzuan Mohd Abd Razak ◽  
...  
Keyword(s):  
Inhibitory Activity ◽  
In Silico ◽  
Rna Binding ◽  
Symptomatic Relief ◽  
Andrographis Paniculata ◽  
Spike Protein ◽  
Rapid Review ◽  
In Silico Studies

Drug repurposing is commonly employed in the search for potential therapeutic agents. Andrographis paniculata, a medicinal plant commonly used for symptomatic relief of the common cold, and its phytoconstituent andrographolide, have been repeatedly identified as potential antivirals against SARS-CoV-2. In light of new evidence emerging since the onset of the COVID-19 pandemic, this rapid review was conducted to identify and evaluate the current SARS-CoV-2 antiviral evidence for A. paniculata, andrographolide, and andrographolide analogs. A systematic search and screen strategy of electronic databases and gray literature was undertaken to identify relevant primary articles. One target-based in vitro study reported the 3CLpro inhibitory activity of andrographolide as being no better than disulfiram. Another Vero cell-based study reported potential SARS-CoV-2 inhibitory activity for both andrographolide and A. paniculata extract. Eleven in silico studies predicted the binding of andrographolide and its analogs to several key antiviral targets of SARS-CoV-2 including the spike protein-ACE-2 receptor complex, spike protein, ACE-2 receptor, RdRp, 3CLpro, PLpro, and N-protein RNA-binding domain. In conclusion, in silico and in vitro studies collectively suggest multi-pathway targeting SARS-CoV-2 antiviral properties of andrographolide and its analogs, but in vivo data are needed to support these predictions.

scholarly journals In silico investigation of potential inhibitors to main protease and spike protein of SARS-CoV-2 in propolis

2021 ◽  
pp. 100969
Author(s):  
Azza H. Harisna ◽  
Rizky Nurdiansyah ◽  
Putri H. Syaifie ◽  
Dwi W. Nugroho ◽  
Kurniawan E. Saputro ◽  
...  
Keyword(s):  
In Silico ◽  
Spike Protein ◽  
Main Protease ◽  
Potential Inhibitors

scholarly journals In Silico Investigation of the New UK (B.1.1.7) and South African (501Y.V2) SARS-CoV-2 Variants with a Focus at the ACE2–Spike RBD Interface

2021 ◽  
Vol 22 (4) ◽  
pp. 1695
Author(s):  
Bruno O. Villoutreix ◽  
Vincent Calvez ◽  
Anne-Geneviève Marcelin ◽  
Abdel-Majid Khatib
Keyword(s):  
Amino Acid ◽  
South African ◽  
In Silico ◽  
Neutralizing Antibodies ◽  
Viral Escape ◽  
Spike Protein ◽  
Amino Acid Substitutions ◽  
The South ◽  
African Strain ◽  
The Uk

SARS-CoV-2 exploits angiotensin-converting enzyme 2 (ACE2) as a receptor to invade cells. It has been reported that the UK and South African strains may have higher transmission capabilities, eventually in part due to amino acid substitutions on the SARS-CoV-2 Spike protein. The pathogenicity seems modified but is still under investigation. Here we used the experimental structure of the Spike RBD domain co-crystallized with part of the ACE2 receptor, several in silico methods and numerous experimental data reported recently to analyze the possible impacts of three amino acid replacements (Spike K417N, E484K, N501Y) with regard to ACE2 binding. We found that the N501Y replacement in this region of the interface (present in both the UK and South African strains) should be favorable for the interaction with ACE2, while the K417N and E484K substitutions (South African strain) would seem neutral or even unfavorable. It is unclear if the N501Y substitution in the South African strain could counterbalance the K417N and E484K Spike replacements with regard to ACE2 binding. Our finding suggests that the UK strain should have higher affinity toward ACE2 and therefore likely increased transmissibility and possibly pathogenicity. If indeed the South African strain has a high transmission level, this could be due to the N501Y replacement and/or to substitutions in regions located outside the direct Spike–ACE2 interface but not so much to the K417N and E484K replacements. Yet, it should be noted that amino acid changes at Spike position 484 can lead to viral escape from neutralizing antibodies. Further, these amino acid substitutions do not seem to induce major structural changes in this region of the Spike protein. This structure–function study allows us to rationalize some observations made for the UK strain but raises questions for the South African strain.

scholarly journals A computational in silico approach to predict high-risk coding and non-coding SNPs of human PLCG1 gene

PLoS ONE ◽  
2021 ◽  
Vol 16 (11) ◽  
pp. e0260054
Author(s):  
Safayat Mahmud Khan ◽  
Ar-Rafi Md. Faisal ◽  
Tasnin Akter Nila ◽  
Nabila Nawar Binti ◽  
Md. Ismail Hosen ◽  
...  
Keyword(s):  
Protein Structure ◽  
T Cell ◽  
Protein Stability ◽  
In Silico ◽  
Catalytic Domain ◽  
Cell Lymphoma ◽  
Computational Study ◽  
Solvent Accessibility ◽  
T Cell Lymphoma ◽  
Post Translational Modification

PLCG1 gene is responsible for many T-cell lymphoma subtypes, including peripheral T-cell lymphoma (PTCL), angioimmunoblastic T-cell lymphoma (AITL), cutaneous T-cell lymphoma (CTCL), adult T-cell leukemia/lymphoma along with other diseases. Missense mutations of this gene have already been found in patients of CTCL and AITL. The non-synonymous single nucleotide polymorphisms (nsSNPs) can alter the protein structure as well as its functions. In this study, probable deleterious and disease-related nsSNPs in PLCG1 were identified using SIFT, PROVEAN, PolyPhen-2, PhD-SNP, Pmut, and SNPS&GO tools. Further, their effect on protein stability was checked along with conservation and solvent accessibility analysis by I-mutant 2.0, MUpro, Consurf, and Netsurf 2.0 server. Some SNPs were finalized for structural analysis with PyMol and BIOVIA discovery studio visualizer. Out of the 16 nsSNPs which were found to be deleterious, ten nsSNPs had an effect on protein stability, and six mutations (L411P, R355C, G493D, R1158H, A401V and L455F) were predicted to be highly conserved. Among the six highly conserved mutations, four nsSNPs (R355C, A401V, L411P and L455F) were part of the catalytic domain. L411P, L455F and G493D made significant structural change in the protein structure. Two mutations-Y210C and R1158H had post-translational modification. In the 5’ and 3’ untranslated region, three SNPs, rs139043247, rs543804707, and rs62621919 showed possible miRNA target sites and DNA binding sites. This in silico analysis has provided a structured dataset of PLCG1 gene for further in vivo researches. With the limitation of computational study, it can still prove to be an asset for the identification and treatment of multiple diseases associated with the target gene.

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