SDM: a server for predicting effects of mutations on protein stability

Pandurangan, Arun Prasad; Ochoa‐Montaño, Bernardo; Ascher, David B.; Blundell, Tom L.

doi:10.1093/nar/gkx439

Cited by 438 publications

(388 citation statements)

References 58 publications

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“…This SNP was also found in most Australian cluster I 2008–2012 epidemic strains that were sequenced (19/22) . Using SWISS‐MODEL and the site directed mutagenesis (SDM) server, the amino acid change in BP3303 was predicted to produce a protein with reduced stability (∆∆G = −2.2). Similarly for ModB, L1191 contains a non‐synonymous SNP at nucleotide position 29 that alters the amino acid from isoleucine to threonine.…”

Section: Discussionmentioning

confidence: 99%

Proteomic Adaptation of Australian Epidemic Bordetella pertussis

et al. 2018

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Bordetella pertussis causes whooping cough. The predominant strains in Australia changed to single nucleotide polymorphism (SNP) cluster I (pertussis toxin promoter allele ptxP3/pertactin gene allele prn2) from cluster II (non-ptxP3/non-prn2). Cluster I was mostly responsible for the 2008-2012 Australian epidemic and was found to have higher fitness compared to cluster II using an in vivo mouse competition assay, regardless of host's immunization status. This study aimed to identify proteomic differences that explain higher fitness in cluster I using isobaric tags for relative and absolute quantification (iTRAQ), and high-resolution multiple reaction monitoring (MRM-hr). A few key differences in the whole cell and secretome were identified between the cluster I and II strains tested. In the whole cell, nine proteins were upregulated (>1.2 fold change, q < 0.05) and three were downregulated (<0.8 fold change, q < 0.05) in cluster I. One downregulated protein was BP1569, a TLR2 agonist for Th1 immunity. In the secretome, 12 proteins were upregulated and 1 was downregulated which was Bsp22, a type III secretion system (T3SS) protein. Furthermore, there was a trend of downregulation in three T3SS effectors and other virulence factors. Three proteins were upregulated in both whole cell and supernatant: BP0200, molybdate ABC transporter (ModB), and tracheal colonization factor A (TcfA). Important expression differences in lipoprotein, T3SS, and transport proteins between the cluster I and II strains were identified. These differences may affect immune evasion, virulence and metabolism, and play a role in increased fitness of cluster I.

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Section: Discussionmentioning

confidence: 99%

Proteomic Adaptation of Australian Epidemic Bordetella pertussis

et al. 2018

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“…This is a crucial step in order to identify the most important regions for protein functionality and thus to understand the effects that mutations associated with retinal disease might have on it. Mutations occurring in a conserved site are assumed to have a greater impact on the correct protein folding 77,78 and, consequently, to alter its functionality. Indeed, phylogenetically conserved sequences in divergent species probably identify a protein region of extreme importance for structural stability.…”

Section: Discussionmentioning

confidence: 99%

A Computational Approach From Gene to Structure Analysis of the Human ABCA4 Transporter Involved in Genetic Retinal Diseases

Trezza

Bernini

Langella

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. The aim of this article is to report the investigation of the structural features of ABCA4, a protein associated with a genetic retinal disease. A new database collecting knowledge of ABCA4 structure may facilitate predictions about the possible functional consequences of gene mutations observed in clinical practice. METHODS.In order to correlate structural and functional effects of the observed mutations, the structure of mouse P-glycoprotein was used as a template for homology modeling. The obtained structural information and genetic data are the basis of our relational database (ABCA4Database). RESULTS.Sequence variability among all ABCA4-deposited entries was calculated and reported as Shannon entropy score at the residue level. The three-dimensional model of ABCA4 structure was used to locate the spatial distribution of the observed variable regions. Our predictions from structural in silico tools were able to accurately link the functional effects of mutations to phenotype. The development of the ABCA4Database gathers all the available genetic and structural information, yielding a global view of the molecular basis of some retinal diseases.CONCLUSIONS. ABCA4 modeled structure provides a molecular basis on which to analyze protein sequence mutations related to genetic retinal disease in order to predict the risk of retinal disease across all possible ABCA4 mutations. Additionally, our ABCA4 predicted structure is a good starting point for the creation of a new data analysis model, appropriate for precision medicine, in order to develop a deeper knowledge network of the disease and to improve the management of patients.

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“…Site Directed Mutator (SDM) is a statistical potential energy function that uses environment-specific amino-acid substitution frequencies within homologous protein families to calculate a stability score, which is analogous to the free energy difference between the wild-type and mutant protein (Pandurangan, Ochoa-Montaño, Ascher, & Blundell, 2017).…”

Section: Structure-based Methodsmentioning

confidence: 99%

Benchmarking analysis of deleterious SNP prediction tools on CYP2D6 enzyme

Ferreira

Fialho

Franco

et al. 2019

Preprint

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The cytochrome P450 family is composed of hemeproteins involved in the metabolic transformation of endogenous and exogenous substances. The CYP2D6 enzyme is responsible for the metabolism of approximately 25% of clinically used drugs and is mainly expressed in the liver. The CYP2D6 gene is known to have a large number of Single Nucleotide Polymorphisms (SNPs) and the majority of them do not present clinical consequences. Nevertheless, these variations could modify the CYP2D6 enzyme's function, resulting in poor metabolizing or ultra-extensive metabolizing phenotypes, when metabolism is slower or accelerated, respectively. Currently, there are several computational tools for predicting functional changes caused by genetic variations. Here, using 20 web servers, we evaluated the impact of 21 missense SNPs (6 neutral and 15 deleterious) previously validated by the literature. Only seven predictors presented sensitivity higher than 70%, while four showed specificity higher than 70% and only one reached the Matthews correlation coefficient of 0.39.Combinations of tools with greater sensitivity and specificity were made to improve the Matthews correlation coefficient, which increased the coefficient of five tools (Provean, FatHMM, SDM, PoPMuSiC and HotMuSiC). The results suggest that the most appropriate tool for CYP2D6 SNP prediction is FATHMM, which could aid in the classification of novel missense SNPs in this gene, providing the identification of mutations potentially associated with drug metabolism.

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SDM: a server for predicting effects of mutations on protein stability

Cited by 438 publications

References 58 publications

Proteomic Adaptation of Australian Epidemic Bordetella pertussis

Proteomic Adaptation of Australian Epidemic Bordetella pertussis

A Computational Approach From Gene to Structure Analysis of the Human ABCA4 Transporter Involved in Genetic Retinal Diseases

Benchmarking analysis of deleterious SNP prediction tools on CYP2D6 enzyme

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