Exciting innovations are being enabled by genomics, with applications from medicine to alternative energy. In order to realize the full potential of genomics, we must be able to understand and interpret genomic data. Genomes for hundreds of organisms have now been sequenced and the 3D structures of over 14,000 newly-discovered gene products – Structural Genomics (SG) proteins – have now been reported. However, most of these SG protein structures are of unknown or uncertain biochemical function. Common approaches to function prediction are informatics based – Is this sequence or structure similar to that of a previously annotated protein in the database? Our approach uses computed chemical properties of the individual amino acids in the protein structure. Large electric fields inside a protein structure alter the acid-base chemistry of active amino acids to enable catalysis. Strong coupling between active-site amino acids and their neighbors, both in and around the active site, impart key properties for catalysis. With these computed chemical properties, protein function is predicted using Structurally Aligned Local Sites of Activity (SALSA). Selected examples from structural genomics are shown, including instances where the previously reported annotation is incorrect and where the SALSA-predicted annotation has been verified by experiment. Examples where the SALSA prediction differs from that of the more conventional informatics-based prediction are highlighted.

Thinking outside the informatics box: Concepts from chemistry for understanding genomes

255th National Meeting (2018)

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