Characterisation, Classification and Conformational Variability of Organic Enzyme Cofactors

Enzymes are the cell’s executive molecules that catalyse the chemical reactions required for an organism to function. Some enzymes require cofactors (metal ions or organic small molecules) for catalysis. Approximately half of all enzyme reactions crucially depend on organic enzyme cofactors. In order to better understand the chemistry of life, it is important to understand the properties, evolutionary context and functional roles of organic enzyme cofactors. The aim of this work is to investigate this important group of compounds. Which molecules are organic enzyme cofactors? What is their molecular function and enzymatic mechanism? What are their physicochemical properties? How are they different from other metabolites in the cell? Are there intrinsic groupings among them? Which enzyme reactions use them? How variable is their conformation in crystallographic protein structures and in solution? How does their conformation vary among homologous proteins? These questions have been investigated using computational methods. The data were extracted manually from the scientific literature and automatically from web resources and has been stored in a database. Statistical methods including uniand multivariate data analysis have been applied to analyse one-dimensional descriptors, two-dimensional structures and functional roles of the cofactor molecules, while the conformational analysis further uses three-dimensional superposition. The results show that organic enzyme cofactors are slightly larger and more polar than the other metabolites although their physicochemical properties sample all of metabolite space. Intrinsic groupings can be identified based on descriptors, two-dimensional structures and molecular functions. Some organic cofactors share common building blocks, which complete and partially complement the functional profile of catalytic amino acids and metal ions. The conformational variability of a cofactor depends on its group membership and can vary substantially from its conformational variability in solution.