Structural Origin of Metal Specificity in Isatin Hydrolase from Labrenzia aggregata Investigated by Computer Simulations.

We performed quantum-chemical calculations, ab initio molecular dynamics, hybrid quantum mechanics/molecular mechanics (QM/MM) and enhanced sampling metadynamics simulations to investigate the origin of metal specificity in isatin hydrolase from Labrenzia aggregata. The peculiar octahedral binding geometry of the Mn2+ ion in the Michaelis complex includes both the isatin substrate and the catalytic water within the first coordination shell of the cation. Our calculations show that the same arrangement of the ligands cannot be efficiently achieved in the presence of other small divalent metal cations such as Zn2+ or Cu2+ . On the contrary, bulkier alkaline-earth cations such as Mg2+ , which allow octahedral coordination, are not able to activate the catalytic water into the stronger OH- nucleophile required to attack the stable N-aryl-amide moiety of isatin.