Understanding Metalloenzymes Mechanisms and Dynamics - PROJECT SUMMARY Metal-containing enzymes or metalloenzymes represent more than 40% of all enzymes and perform a wide variety of chemical transformations in cells with great biomedical importance. The unique functionalities of the metalloenzymes result from the amazing synergy between the properties of the metal center, the coordinated biological ligands, and last but not least, the unique effects of the second coordination sphere (SCS) and long-range (LR) interactions with the protein and its dynamics. Among the diverse classes of metalloenzymes, the Zn(II)-containing matrix metalloproteinases (MMPs) and Fe(II)/2-oxoglutarate (2OG)-dependent oxygenases are in special interest due to their intriguing structure-function relationships and biomedical importance. Although both sets of metalloenzymes have been intensively studied and important aspects of their structure-function relationships have been elucidated, there are a lot of missing points that demand comprehensive investigation in the directions of revealing their catalytic mechanisms, understanding the effects of the SCS and LR-interacting residues and elucidating the correlation between the dynamics and catalysis. Providing the missing knowledge on the two groups of metalloenzymes applying computational chemistry methods in correlation to experiments is the long-term focus of the proposed research. The outcomes will contribute to understanding the mechanisms of metalloenzymes, will provide missing elements to the enzyme redesign protocols, and will help for the design of effective and specific enzyme inhibitors.
