In QM/MM calculation (Figs. and), the A + is observed to bind within a hydrophobic active pocket comprising aromatic residues (F64, F93, F221, W335, and H339), hydrophobic residues (I59, A189, G216, V218, I254, V343, and P344), and polar residues (C253 and S338). Notably, A + exhibits a unique structural feature wherein C1, C10, and C11 form a triangular "protonated cyclopropane" configuration, which is extensively reported in previous research . The C1-C10 and C1-C11 distances are 1.62 Å and 1.89 Å respectively (Supplementary Figure ), which are longer than the typical C-C single bond but shorter than the van der Waals radius of two carbon atoms, suggesting significant hyperconjugation effects between the C1-C10 σ bond and the C11's vacant p-orbital. Additionally, A + is stabilized by a dipolar interaction between positively charged C11 and C14=C15, with a distance of 3.07 Å (Supplementary Figure ). The hydrogen (Ha) on C1 resides above the p-orbital of C11, with a Ha-C11 distance of 1.82 Å, thus facilitating the subsequent 1,3-hydride shift (Supplementary Figure ). Following Ha's shift from C1 and to C11, an allylic secondary carbocation forms, leaving C1 positively charged. Then C1 moves towards C6 to initiate a 1,6-cyclization, resulting in the formation of B + . Concurrently, the distance between C11 and C14=C15 elongates to 3.34 Å, as the positive charge shifts to C7 (Supplementary Figure ). The C7 + is stabilized by the nearby aromatic residue F221, with an interaction energy of 4.4 kcal/mol. Herein the hydride shift and cyclization represent a concerted but asynchronous process, requiring only a slight energy barrier of 1.8 kcal/mol while releasing a significant heat of 23.5 kcal/mol (Supplementary Figure ), making it both kinetically and thermodynamically very feasible.