Enzymes continue to be the subject of intensive research efforts because of their ability to accelerate chemical reactions by factors as large as 1020 with extraordinary selectivity. 1 Despite enormous advances, on both experimental and theoretical fronts, our understanding of how proteins catalyze reactions remains incomplete. Biomimetic and engineered protein catalysts have failed to reach the catalytic efficiency of naturally occurring enzymes. In addition, computational methods continue to fall short of predicting with precision the catalytic properties of known structures, and the more ambitious goal of generating de noVo enzymes with desired function. Evidently, the ultimate goal of using and engineering enzymes for biomedical and industrial applications still demands a deeper understanding of how the primary sequence of a protein determines its catalytic properties. This review is intended to provide insight …