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1	Searching for novel protein-protein specificities using a combined approach of sequence co-evolution and local structural equilibration Nordesjö, Olle January 2016 (has links) Greater understanding of how we can use protein simulations and statistical characteristics of biomolecular interfaces as proxies for biological function will make manifest major advances in protein engineering. Here we show how to use calculated change in binding affinity and coevolutionary scores to predict the functional effect of mutations in the interface between a Histidine Kinase and a Response Regulator. These proteins participate in the Two-Component Regulatory system, a system for intracellular signalling found in bacteria. We find that both scores work as proxies for functional mutants and demonstrate a ~30 fold improvement in initial positive predictive value compared with choosing randomly from a sequence space of 160 000 variants in the top 20 mutants. We also demonstrate qualitative differences in the predictions of the two scores, primarily a tendency for the coevolutionary score to miss out on one class of functional mutants with enriched frequency of the amino acid threonine in one position. Biotechnology Bioinformatics Molecular Structure Protein Conformation Computing Methodologies Protein-protein interaction Binding affinity Mutation analysis Amino acid mutation in-silico binding affinity prediction Two-component regulatory system Histidine Kinase Response Regulator Prediction PhoQ PhoP Phosphatase Bioinformatics and Systems Biology Bioinformatik och systembiologi Structural Biology Strukturbiologi Bioinformatics (Computational Biology) Bioinformatik (beräkningsbiologi)

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Searching for novel protein-protein specificities using a combined approach of sequence co-evolution and local structural equilibration