Artificial Super‐Receptor Interface Mimic and Exceed Protein Functionality

ABSTRACT Active sites in proteins account for a small proportion but are crucial for their enhanced binding affinity and specificity, making related biomimetic structures a research hotspot. However, current structures greatly depended on rigid inorganic frameworks for high‐certainty assembly, which introduced interfering inorganic groups and interactions not present in proteins. To address this, we utilized organic crystal rigidity to achieve high‐certainty assembly conformations. Thus periodic active sites at crystal interface can be precisely assembled by pure organic units. Our three‐step strategy for designing artificial super‐receptors includes: (1) Learning active site model from proteins; (2) Imitating active sites in crystal cell unit; (3) Exceeding natural performance with periodic active sites at the crystal interface. Practically, by mimicking the human dopamine transporter (amphetamine drug receptor), our artificial super‐receptor acted as super‐sensor. It achieved a limit of detection down to 480 pM, 64,580 times lower than the natural receptor. It also showed revolutionary broad‐spectrum specificity for amphetamine drugs, including chiral methamphetamine, ecstasy, and even potential novel amphetamine derivative illicit drugs, allowing active preventing detection for the drug abuse problem. The customized designing strategy was also validated by high dopamine sensitivity (2.8 nM) and selectivity of d‐DAT inspired PySO 3 H artificial super‐receptor. Such strategy can be further extended to other functional proteins for various super‐performance, from sensor, catalyst, medicine, agriculture to therapeutic applications, etc.