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Computational predictions of the mutant behavior of AraC.

ABSTRACT: An algorithm implemented in Rosetta correctly predicts the folding capabilities of the 17-residue N-terminal arm of the AraC gene regulatory protein when arabinose is bound to the protein and the dramatically different structure of this arm when arabinose is absent. The transcriptional activity of 43 mutant AraC proteins with alterations in the arm sequences was measured in vivo and compared with their predicted folding properties. Seventeen of the mutants possessed regulatory properties that could be directly compared with folding predictions. Sixteen of the 17 mutants were correctly predicted. The algorithm predicts that the N-terminal arm sequences of AraC homologs fold to the Escherichia coli AraC arm structure. In contrast, it predicts that random sequences of the same length and many partially randomized E. coli arm sequences do not fold to the E. coli arm structure. The high level of success shows that relatively "simple" computational methods can in some cases predict the behavior of mutant proteins with good reliability.

SUBMITTER: Berrondo M

PROVIDER: S-EPMC2873782 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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Computational predictions of the mutant behavior of AraC.

Berrondo Monica M Gray Jeffrey J JJ Schleif Robert R

Journal of molecular biology 20100323 3

An algorithm implemented in Rosetta correctly predicts the folding capabilities of the 17-residue N-terminal arm of the AraC gene regulatory protein when arabinose is bound to the protein and the dramatically different structure of this arm when arabinose is absent. The transcriptional activity of 43 mutant AraC proteins with alterations in the arm sequences was measured in vivo and compared with their predicted folding properties. Seventeen of the mutants possessed regulatory properties that co ...[more]

PMID: 20338183

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Project description:The advent of rapid whole-genome sequencing has created new opportunities for computational prediction of antimicrobial resistance (AMR) phenotypes from genomic data. Both rule-based and machine learning (ML) approaches have been explored for this task, but systematic benchmarking is still needed. Here, we evaluated four state-of-the-art ML methods (Kover, PhenotypeSeeker, Seq2Geno2Pheno and Aytan-Aktug), an ML baseline and the rule-based ResFinder by training and testing each of them across 78 species-antibiotic datasets, using a rigorous benchmarking workflow that integrates three evaluation approaches, each paired with three distinct sample splitting methods. Our analysis revealed considerable variation in the performance across techniques and datasets. Whereas ML methods generally excelled for closely related strains, ResFinder excelled for handling divergent genomes. Overall, Kover most frequently ranked top among the ML approaches, followed by PhenotypeSeeker and Seq2Geno2Pheno. AMR phenotypes for antibiotic classes such as macrolides and sulfonamides were predicted with the highest accuracies. The quality of predictions varied substantially across species-antibiotic combinations, particularly for beta-lactams; across species, resistance phenotyping of the beta-lactams compound, aztreonam, amoxicillin/clavulanic acid, cefoxitin, ceftazidime and piperacillin/tazobactam, alongside tetracyclines demonstrated more variable performance than the other benchmarked antibiotics. By organism, Campylobacter jejuni and Enterococcus faecium phenotypes were more robustly predicted than those of Escherichia coli, Staphylococcus aureus, Salmonella enterica, Neisseria gonorrhoeae, Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii, Streptococcus pneumoniae and Mycobacterium tuberculosis. In addition, our study provides software recommendations for each species-antibiotic combination. It furthermore highlights the need for optimization for robust clinical applications, particularly for strains that diverge substantially from those used for training.

Dataset Information

Computational predictions of the mutant behavior of AraC.

Publications

Computational predictions of the mutant behavior of AraC.

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