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Published on: February 23, 2014
Bioinformatics analysis of wild-type ParC and S79F, S79Y mutations in Streptococcus pneumoniae
1Department of Medical Microbiology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey. akgund@istanbul.edu.tr.
Objective:
S79Y and S79F mutations in ParC at the fluoroquinolone binding site confer resistance to quinolones in Streptococcus pneumoniae. The aim of this study was to perform bioinformatics analysis of wild-type and mutant ParC identified in S. pneumoniae strains.
Materials And Methods:
Homology models were created with Swiss Model, and the UCSF Chimera was used for the analysis and evaluation of the models. Molecular docking studies and protein-ligand interaction analysis were performed using CB-Dock developed by AutoDock Vina and Protein Ligand Interaction Profiler (PLIP), respectively.
Results:
According to the homology modeling results, changes were observed in the physicochemical properties. Both mutant types showed a decrease in hydrophobicity (S79F: 2.0, S79Y: 0.5 - Kyte-Doolittle) and an increase in regional volume (S79F: 95 Å3, S79Y: 100 Å3). The docking scores for the wild-type, S79F, and S79Y types were 6.3, 4.9, and 5.0, respectively. The decrease in docking scores indicates weaker binding in the mutant types. The results of the PLIP analysis indicate that new bonds were formed, and the bond types changed in both mutant types, while some bonds disappeared.
Conclusions:
It is believed that the change in physicochemical properties caused by the mutation altered the conformation of the quinolone binding region and the bond types, numbers, and proximities of the amino acids involved in the interaction with the active substance. The results obtained from the modeling performed in this study with visualization and analysis of possible conformational, hydrophobic, and volumetric changes of only ParC mutations provided data and literature support to elucidate the mechanism. The molecular docking and PLIP results obtained in this study support both the homology modeling results and the fact that S79F and S79Y have been shown to be resistant in the literature.
Insights
Bioinformatics analysis revealed that S79Y and S79F mutations in Streptococcus pneumoniae ParC alter protein structure, reducing quinolone binding affinity. These ParC mutations are linked to quinolone resistance in this bacterium.
Area of Science:
- Microbiology
- Computational Biology
- Drug Resistance
Background:
- Quinolone antibiotics are crucial for treating Streptococcus pneumoniae infections.
- Mutations in the ParC protein, specifically at the fluoroquinolone binding site, are a known mechanism of quinolone resistance.
- Understanding the molecular basis of these mutations is essential for developing effective treatment strategies.
Purpose of the Study:
- To investigate the impact of S79Y and S79F mutations in Streptococcus pneumoniae ParC on protein structure and function using bioinformatics.
- To elucidate the mechanism by which these ParC mutations confer resistance to quinolone antibiotics.
Main Methods:
- Homology modeling of wild-type and mutant ParC proteins using Swiss Model.
- Structural analysis and visualization with UCSF Chimera.
- Molecular docking studies with CB-Dock (AutoDock Vina) to assess binding affinity.
- Protein-ligand interaction analysis using Protein Ligand Interaction Profiler (PLIP).
Main Results:
- Homology modeling indicated changes in physicochemical properties, including decreased hydrophobicity and increased regional volume in both S79F and S79Y mutants.
- Molecular docking revealed reduced binding scores for mutants (S79F: 4.9, S79Y: 5.0) compared to wild-type (6.3), suggesting weaker interactions.
- PLIP analysis showed altered, newly formed, and disappeared bonds between the mutant ParC proteins and the quinolone binding site.
Conclusions:
- The observed changes in physicochemical properties, conformation, and binding interactions of the ParC protein due to S79Y and S79F mutations explain the reduced affinity for quinolones.
- These bioinformatics findings support the documented quinolone resistance associated with S79F and S79Y mutations in Streptococcus pneumoniae.
- The study provides molecular insights into the mechanism of quinolone resistance mediated by ParC mutations.
