Analysis of the Structure-Function-Dynamics Relationships of GALT Enzyme and of Its Pathogenic Mutant p.Q188R: A Molecular Dynamics Simulation Study in Different Experimental Conditions

Verdino, Anna; D’Urso, Gaetano; Tammone, Carmen; Scafuri, Bernardina

doi:10.3390/molecules26195941

Cited by 5 publications

(3 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For each spike–antibody ensemble selected from PDB, we first analyzed the interactions at the interfaces between the residues belonging to each chain of spike and each antibody chain, using an in-house R script to automatize the calculation of all possible combinations between each spike chain and each antibody chain. The interactions at the interface were analyzed by LigPlot+/DIMPLOT [ 21 ] and an in-house Perl script previously developed [ 22 , 23 ] to predict the presence of salt bridges following the criteria of Kumar and Nussinov [ 18 ] and to filter the interface interactions.…”

Section: Methodsmentioning

confidence: 99%

In Silico Analysis of the Effects of Omicron Spike Amino Acid Changes on the Interactions with Human Proteins

et al. 2022

Self Cite

View full text Add to dashboard Cite

The SARS-CoV-2 variant Omicron is characterized, among others, by more than 30 amino acid changes occurring on the spike glycoprotein with respect to the original SARS-CoV-2 spike protein. We report a comprehensive analysis of the effects of the Omicron spike amino acid changes in the interaction with human antibodies, obtained by modeling them into selected publicly available resolved 3D structures of spike–antibody complexes and investigating the effects of these mutations at structural level. We predict that the interactions of Omicron spike with human antibodies can be either negatively or positively affected by amino acid changes, with a predicted total loss of interactions only in a few complexes. Moreover, our analysis applied also to the spike-ACE2 interaction predicts that these amino acid changes may increase Omicron transmissibility. Our approach can be used to better understand SARS-CoV-2 transmissibility, detectability, and epidemiology and represents a model to be adopted also in the case of other variants.

show abstract

Section: Methodsmentioning

confidence: 99%

In Silico Analysis of the Effects of Omicron Spike Amino Acid Changes on the Interactions with Human Proteins

et al. 2022

Self Cite

View full text Add to dashboard Cite

show abstract

“…6LZG and 6M0J, by using Modeller [Sali and Blundell, 1993]. For PDB complexes as well as modelled complexes the interactions at the interface were analyzed by LigPlot+/DIMPLOT [Laskowski and Swindells, 2011], and an in-house Perl script previously developed [Verdino et al, 2021a,b], to predict the presence of salt bridges following the criteria of [Kumar and Nussinov, 1999] and to filter the interface interactions.…”

Section: Methodsmentioning

confidence: 99%

In Silico Analysis Of The Effects Of Omicron Spike Amino Acid Changes On The Interactions With Human ACE2 Receptor And Structurally Characterized Complexes With Human Antibodies

D'Arminio

Giordano

Scafuri

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

The new SARS-CoV-2 variant Omicron is characterised, among others, by more than 30 amino acid changes (including 4 deletions and 1 insertion) occurring on the spike glycoprotein. We report a comprehensive analysis of the effects of the Omicron spike amino acid changes in the interaction with human ACE2 receptor or with human antibodies, obtained by analysing the publicly available resolved 3D structures. Our analysis predicts that amino acid changes occurring on amino acids interacting with the ACE2 receptor can increase Omicron transmissibility. The interactions of Omicron spike with human antibodies can be both negatively and positively affected by amino acid changes, with a predicted total loss of interactions only in few complexes. We believe that such an approach can be used to better understand SARS-CoV-2 transmissibility, detectability, and epidemiology, especially when extended to other than spike proteins.

show abstract

“…A rising trend in medical research has been the use of computer-generated predictive models to detect and categorize the impact of mutations on protein structure and enzymatic activity. Utilizing predictive modeling, researchers can potentially predict which mutations are most likely to cause enzymatic dysfunction and lead to disease [ 4 ]. This information can help guide research strategies to be more efficient and resource-preserving by focusing on the most impactful mutations.…”

Section: Introductionmentioning

confidence: 99%

Comparison of In Vitro and In Silico Assessments of Human Galactose-1-Phosphate Uridylyltransferase Coding Variants

Mitchell¹,

Johnson²

2023

Cureus

View full text Add to dashboard Cite

Human pathogenic coding variations of the galactose-1-phosphate uridylyltransferase (GALT) gene cause classic galactosemia, a recessive disease of galactose metabolism. Unfortunately, there are many variants of uncertain significance (VUS) that need to be characterized in order to be able to predict the likelihood of classic galactosemia for all possible genotypes. There are many bioinformatic resources available that attempt to predict the pathogenicity of a human variant, but it is unclear if these methods realistically predict the consequence of these variants. To determine the clinical application of these resources, we compared the results of in vitro enzymatic assays with in silico predictive models. MethodsIn all assays, we compared the activity of the three human GALT VUS (Alanine81Threonine, Histidine47Aspartate, Glutamate58Lysine) to native GALT (nGALT) and to a variant of known pathogenic clinical significance (Glutamine188Arginine). The enzymatic activities of VUS recombinant proteins were compared to the results of in silico analytical methods. The in silico methods included the comparison of molecular dynamic simulation root-mean-square deviation (RMSD) results and the results from predictive programs PredictSNP, evolutionary model of variant effect (EVE), ConSurf, and sorting intolerant from tolerant (SIFT). ResultsThe enzymatic assays showed that the variants tested had diminished Vmax relative to native protein. The VUS RMSD data for both the whole protein and individual residues in the molecular dynamics simulations were not significantly different when compared to nGALT. The other predictive programs had mixed results for each VUS and were not consistent with the enzyme activity or simulation results. ConclusionsOur experiments indicated a statistically significant decrease in enzymatic activity of the VUS when compared to nGALT. These experiments also demonstrated significant differences between in silico predictions and in vitro results. These results suggest that the in silico tools used may not be beneficial in determining pathogenicity of GALT VUS.

show abstract

Analysis of the Structure-Function-Dynamics Relationships of GALT Enzyme and of Its Pathogenic Mutant p.Q188R: A Molecular Dynamics Simulation Study in Different Experimental Conditions

Cited by 5 publications

References 35 publications

In Silico Analysis of the Effects of Omicron Spike Amino Acid Changes on the Interactions with Human Proteins

In Silico Analysis of the Effects of Omicron Spike Amino Acid Changes on the Interactions with Human Proteins

In Silico Analysis Of The Effects Of Omicron Spike Amino Acid Changes On The Interactions With Human ACE2 Receptor And Structurally Characterized Complexes With Human Antibodies

Comparison of In Vitro and In Silico Assessments of Human Galactose-1-Phosphate Uridylyltransferase Coding Variants

Contact Info

Product

Resources

About