Using evolutionary sequence variation to make inferences about protein structure and function

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• Colwell, L (University of Cambridge)
• Monday 17 March 2014, 14:30-15:10
• Seminar Room 1, Newton Institute.

If you have a question about this talk, please contact Mustapha Amrani.

Institute distinguished event

The explosive growth in the number of protein sequences gives rise to the possibility of using natural variation in sequences of homologous proteins to find residues that control different protein phenotypes. Because in many cases phenotypic changes are controlled by a group of residues, the mutations that separate one phenotype from another will be correlated. We show that correlations between amino acid mutations at different sites in a protein can be used to predict, de novo, tertiary protein structure of both globular and transmembrane proteins from large sequence alignments.

In addition, residues that determine the specificity of protein interactions can be identified from inter-protein residue pairs that co-vary. Those amino acids whose mutation patterns are most highly constrained by evolution are found to often involve known functional sites of proteins, such as enzyme active sites, and ligand binding sites. These findings raise questions about the relationship between protein structure and function, and the evolutionary constraints that this relationship imposes on different proteins.

Our maximum entropy based analysis identifies a global probability with a minimal set of amino acid pair interactions that reproduce all the observed pairwise correlations in the data. The resulting probability model for the sequence of the protein of interest raises the possibility that we may be able to identify amino acids that control different protein phenotypes, and hence re-programme existing proteins.

This talk is part of the Isaac Newton Institute Seminar Series series.

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