For the QM cluster model, the atom selection was done following the previous work of Himo's group. The only difference is that we added all backbone atoms for residue 12 (the position that is mutated in variant F12Y), allowing for additional flexibility and ring rotation. Geometry minimizations were performed using Gaussian16 63 , using the hybrid density functional theory method B3LYP , and the 6-31G(d,p) basis set. All energies were calculated by performing single-point calculations on the optimized B3LYP/6-31G(d,p) geometries using the M06-2x functional and Def2TZVPP basis set (M06-2X/Def2TZVPP//B3LYP/6-31G(d,p)). Solvation effects were considered using the SMD solvation model, a variation of Truhlar's and coworkers' integral equation formalism variant (IEFPCM) , using diethyl ether as solvent.