“…Proteins have been previously computationally designed to bind new ligands, 1 proteins, 2 and nucleic acids, 3 to improve protein stability, 4,5 as well as to introduce novel enzymatic activity, 6,7 demonstrating that the fundamental rudiments of molecular recognition can adequately be captured via computational design. The systematic fine-tuning of molecular recognition between proteins and ligands finds many biotechnological applications ranging from improved catalytic activity, 8 improved protein thermostability, [9][10][11] genetic circuits, 12 biosensors, 13,14 chiral separations, 15 the construction of novel enzymes with alternative functionality, 16,17 the creation of gene switches 18 and signal transduction pathways. 19,20 Many of the aforementioned applications require the enzymes to operate under unnatural conditions (e.g., at elevated temperatures or in nonaqueous environments), and/or possess altered cofactor or substrate specificity.…”