Metabolic biochemical reactions are performed by proteins. Knowledge of their 3D structure has been proven critical to understand the molecular effect of variations in the amino acid sequence on their catalytic activity, and thus desired phenotypic changes are often delivered through modification in protein function. The effect of functional polymorphisms will be modelled at the protein structure level for the key players in metabolic pathways. The effect of mutations on the dynamics and kinetics of the protein will be modelled to inform design strategies. Ligand and protein-protein interactions will be simulated and integrated with biochemical modelling using a multiscale strategy.
We aim at providing a set of computational tools for the selection of mutations for adaptive improvement of E. coli to confer susceptibility to selected antibiotics. The tool will comprise a database of naturally evolved mutations from E. coli strains (provided by the MBE cluster) mapped on the bacterial 3D protein-protein interaction network (PPIN) and a predictive software to mine the database for candidate mutations with potential to confer adaptive and desired phenotypes when combined.
We are developing a database protein structures, interactions and mutations. The most recent and comprehensive PPIN for E. coli has been used as reference. Experimental structures have been integrated with theoretical models.
The core genome from Brunel E. coli strain collection has been mapped to the PPIN and the unique set of 3D proteins structures for the core genome have been used to populate a relational database. A mapping of non-synonymous mutations in coding regions from naturally evolved E. coli strains is in progress. Each protein entry will contain information on mutations, associated strains and experimental conditions.
Structural models of proteins with selected mutations will form a library of design templates that will be integrated into multilevel biochemical network models with desired phenotypic behaviours.