Enzymes catalyze reactions under mild conditions that would otherwise require extreme conditions such as high temperature or strong acidity or basicity. To achieve this, enzymes often impart reactive chemical properties to amino acid sidechains that are far less reactive in the absence of the protein environment. In the enzymatic environment, active site amino acid sidechains that are weak Brønsted acids or bases in a small peptide can transform into a strong acid or base. The computed electrostatic and proton transfer properties are studied for 20 enzymes that represent all six major EC classes and a variety of different folds. The properties of aspartate, glutamate, and lysine residues that have been previously experimentally determined to be catalytically active are reported. All catalytic aspartate and glutamate residues studied here are strongly coupled to at least one other aspartate or glutamate residue and often to multiple other carboxylate residues with intrinsic pK differences less than 1 pH unit. Sometimes these catalytic acidic residues are also coupled to a histidine residue, such that the intrinsic pK of the acidic residue is higher than that of the histidine. All catalytic lysine residues studied here are strongly coupled to tyrosine or cysteine residues, wherein the intrinsic pK of the anion-forming residue is higher than that of the lysine. Some catalytic lysines are also coupled to other lysines with intrinsic pK differences within 1 pH unit. Some evidence of the possible types of interactions that facilitate nucleophilicity is discussed. The interactions reported here provide important clues about how side chain functional groups that are weak Brønsted acids or bases for the free amino acid in solution can become strong acids, bases or nucleophiles in the enzymatic environment. Such interactions are important considerations in enzyme design.

Electrostatic fingerprints of catalytically active amino acids in enzymes

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