QMEANDisCo—distance constraints applied on model quality estimation

Studer, Gabriel; Rempfer, Christine; Waterhouse, Andrew; Gumienny, Rafal; Haas, Juergen; Schwede, Torsten

doi:10.1093/bioinformatics/btz828

Cited by 651 publications

(410 citation statements)

References 39 publications

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“…QMEANDisCO (Studer et al, 2020), which uses distance restraints calculated from experimental structures of proteins homologous to the query protein and returns a plot of local IDDT (distance difference comparison) scores for each residue between 0 and 1. A global IDTT >0.6 indicates a good model structure.…”

Section: Methodsmentioning

confidence: 99%

Structure, function and variants analysis of the androgen-regulatedTMPRSS2, a drug target candidate for COVID-19 infection

David

Khanna

Beykou

et al. 2020

Preprint

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SARS-CoV-2 is a novel virus causing mainly respiratory, but also gastrointestinal symptoms. Elucidating the molecular processes underlying SARS-CoV-2 infection, and how the genetic background of an individual is responsible for the variability in clinical presentation and severity of COVID-19 is essential in understanding this disease.Cell infection by the SARS-CoV-2 virus requires binding of its Spike (S) protein to the ACE2 cell surface protein and priming of the S by the serine protease TMPRSS2. One may expect that genetic variants leading to a defective TMPRSS2 protein can affect SARS-CoV-2 ability to infect cells. We used a range of bioinformatics methods to estimate the prevalence and pathogenicity of TMPRSS2 genetic variants in the human population, and assess whether TMPRSS2 and ACE2 are co-expressed in the intestine, similarly to what is observed in lungs.We generated a 3D structural model of the TMPRSS2 extracellular domain using the prediction server Phyre and studied 378 naturally-occurring TMPRSS2 variants reported in the GnomAD database. One common variant, p.V160M (rs12329760), is predicted damaging by both SIFT and PolyPhen2 and has a MAF of 0.25. Valine 160 is a highly conserved residue within the SRCS domain. The SRCS is found in proteins involved in host defence, such as CD5 and CD6, but its role in TMPRSS2 remains unknown. 84 rare variants (53 missense and 31 leading to a prematurely truncated protein, cumulative minor allele frequency (MAF) 7.34×10−4) cause structural destabilization and possibly protein misfolding, and are also predicted damaging by SIFT and PolyPhen2 prediction tools. Moreover, we extracted gene expression data from the human protein atlas and showed that both ACE2 and TMPRSS2 are expressed in the small intestine, duodenum and colon, as well as the kidneys and gallbladder.The implications of our study are that: i. TMPRSS2 variants, in particular p.V160M with a MAF of 0.25, should be investigated as a possible marker of disease severity and prognosis in COVID-19 and ii. in vitro validation of the co-expression of TMPRSS2 and ACE2 in gastro-intestinal is warranted.

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Section: Methodsmentioning

confidence: 99%

Structure, function and variants analysis of the androgen-regulatedTMPRSS2, a drug target candidate for COVID-19 infection

David

Khanna

Beykou

et al. 2020

Preprint

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“…Qualitative Model Energy Analysis (QMEAN): The composite estimator of the different geometrical properties of the protein sequence that provides both global (for the entire structure) and local (per residue) absolute quality estimates based on one single model [18,19].…”

Section: Methodsmentioning

confidence: 99%

“…The QMEAN Z-score estimates the "degree of nativeness" of the structural features observed in the model on a global scale. The QMEAN Z-score compares the model QMEAN score to the scores of the similar size expected experimental structures, through Cβ atoms only, all atoms, the solvation potential, and the torsion angle potential [18,19].…”

Section: Methodsmentioning

confidence: 99%

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The physicochemical and phylogenetic properties of twelve spike glycoprotein models for SARS-CoV-2 from China, Iran, and Tunisia

Odhaib

Al-Aubaidy

2020

Preprint

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Background The coronavirus spike glycoprotein is a trimeric structural surface protein that facilitates the viral adhesion through attaching receptors on the human cell surface. This study aims to analyse and compare the genomic and phylogenetic properties of these spike glycoproteins from China, Iran, and Tunisia. Methods This is a descriptive cross-sectional comparative study for the different properties of S glycoprotein from 12 SARS-CoV-2 specimens from GenBank. Clustal Omega was used to study model sequences alignment, residual conservation, phylogeny, and identity matrix. SWISS-MODEL developed and validated the 3D models for three protein sequences with the highest model quality. The different physicochemical characteristics of different models were assessed by ExPASy proteomics. Results The Chinese and the Iranian sequences share 100% identity, although they have a different amino acids number, and 25-29.27% identity to the Tunisian sequences. The 12 models are monophyletic, with varying stages of evolutionary divergence. There are six fully, three highly, and five lowly conserved residues across the sequences. The resulting three highly reliable 3D models were of different global qualities, being the lowest for the Tunisian, and the highest for the Iranian models. All the models are highly hydrophilic. The Tunisian models were unstable in comparison to the relatively stable other models with different physicochemical characteristics. Conclusion The models had different N-terminal residues and side groups polarity and charge. The S glycoproteins are not identical nor unique in model structure nor the physicochemical profiles in different parts of the world. The Tunisian models are drastically biodiverse from the Chinese and Iranian models.

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“…COVID-2019-HR1P1 and COVID-2019-HR2P1 peptide sequences are imported to SWISS-MODEL (https://swissmodel.expasy.org) [4][5][6][7][8]. It builds the models by aligning with existing protein sequences before exporting the predicted 3D structure.…”

Section: From Sequence To 3d Structurementioning

confidence: 99%

Designed peptides as potential fusion inhibitors against SARA-CoV-2 coronavirus infection

Chen

Bai

Zou

et al. 2020

Preprint

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Inspired by fusion-inhibitory peptides from heptad repeat 1 (HR1) and heptad repeat 2 (HR2) domains from human immuno-deficiency virus type 1 (HIV-1) envelope glycoprotein gp41 and severe acute respiratory syndrome-coronavirus (SARS-CoV) based on viral fusogenic mechanism in the present work, we provided a similar approach to design the synthesized peptides against the entry into host cells of SARA-CoV-2 virus that causes 2019 novel coronavirus disease . These peptides derived from HR1 and HR2 of SARA-CoV-2 spike protein were further tested for their interaction and potential fusion possibility through circular dichroism spectrum. Here we used the peptide COVID-2019-HR1P1 (40 amino acids) as the target, which was derived from HR1 of SARA-CoV-2 spike protein, while the designed peptides including COVID-2019-HR2P1 (37 amino acids), COVID-2019-HR2P2 (32 amino acids) and others derived from HR2 of SARA-CoV-2 were tested for their binding to COVID-2019-HR1P1. Interestingly, results showed that both COVID-2019-HR2P1 and COVID-2019-HR2P2 can form the complex with COVID-2019-HR1P1, respectively. This implied that these designed peptides could play an important role in blocking SARA-CoV-2 entry into mammalian host cells via viral fusogenic mechanism, and thus could be used for preventing SARA-CoV-2 infection.

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QMEANDisCo—distance constraints applied on model quality estimation

Cited by 651 publications

References 39 publications

Structure, function and variants analysis of the androgen-regulatedTMPRSS2, a drug target candidate for COVID-19 infection

Structure, function and variants analysis of the androgen-regulatedTMPRSS2, a drug target candidate for COVID-19 infection

The physicochemical and phylogenetic properties of twelve spike glycoprotein models for SARS-CoV-2 from China, Iran, and Tunisia

Designed peptides as potential fusion inhibitors against SARA-CoV-2 coronavirus infection

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