Investigation of Allosteric Mechanism from an Evolutionary Perspective*

Allostery is fundamental to biological regulation and, consequently, understanding its molecular mechanism has many potential practical applications. Investigation of the evolution of allostery offers one approach to elucidating this mechanism. Biotin protein ligases are essential for survival in all organisms. In bacteria the Class I ligases are non-allosteric whereas Class II ligases are allosteric. Both classes show significant structural and sequential similarity. So the question arises: what is the origin of allostery in Class II ligases? In this work, we used concepts from Network theory and applied bioinformatic tools to identify features that distinguish allosteric from non-allosteric biotin ligases. Energy-based network analysis performed on the MD trajectories of allosterically "inactive" and "active" forms of each protein class representative revealed distinct residue networks that show different responses to allosteric ligand binding. Phylogenetic Mutual Information analysis revealed markedly distinct residue coevolution patterns in the two ligase classes. The combined results reveal that allostery can evolve via changes in the composition of residue networks in a protein and the patterns of interaction among these networks.