Understanding the Role of Hydrogen Bonds and Other Non-Covalent Interactions in Enzymatic Catalysis*

Atomistic computational simulations have become a useful tool for biomolecular research. These tools are now becoming sufficiently accurate to investigate enzymatic reactions with atomic resolution and to predict catalytic features that can arise in these systems. Here, I will present the use of computational approaches to investigate how internal and external factors can impact enzymatic catalysis via two example systems. The first example involves the investigation of the role of an ordered water molecule located in the second coordination shell of the Ferryl group of two Fe(II)/α-ketoglutarate (Fe/α-KG) superfamily enzymes in the rate limiting step of the reaction. Our calculations suggest a significant impact of this water molecule on the reaction mechanism and how one single hydrogen bond oriented toward the oxo group can activate the reaction. The second example involves the comparison of the reaction mechanism of the elementary step from compound-1 to compound-2 in the heme-based active site of horseradish peroxidase (HRP) in water and in a water/ionic-liquid mixture to determine the impact of the solvent on the reaction mechanism. Our simulations suggest a significant role of the solvent on the structure and electronic environment of the active site. The details of the specific impacts of a single hydrogen bond, or multiple interactions due to different solvent environments on specific enzymatic catalytic mechanisms will be presented and discussed.