Prediction of the three-dimensional structures of the biotinylated domain from yeast pyruvate carboxylase and of the lipoylated H-protein from the pea leaf glycine cleavage system: a new automated method for the prediction of protein tertiary structure.

A new, automated, knowledge-based method for the construction of three-dimensional models of proteins is described. Geometric restraints on target structures are calculated from a consideration of homologous template structures and the wider knowledge base of unrelated protein structures. Three-dimensional structures are calculated from initial partly folded states by high-temperature molecular dynamics simulations followed slow cooling of the system (simulated annealing) using nonphysical potentials. Three-dimensional models for the biotinylated domain from the pyruvate carboxylase of yeast and the lipoylated H-protein from the glycine cleavage system of pea leaf were constructed, based on the known structures of two lipoylated domains of 2-oxo acid dehydrogenase multienzyme complexes. Despite their weak sequence similarity, the three proteins are predicted to have similar three-dimensional structures, representative of a new protein module. Implications for the mechanisms of posttranslational modification of these proteins and their catalytic function are discussed.