Minchao Fang

De novo design of small molecule–regulated protein oligomers @ScienceMagazine 1. Researchers have developed a novel computational method to design protein oligomers regulated by small molecules, focusing on the FDA-approved drug amantadine. This approach enables precise control over protein assembly, offering potential applications in biotechnology and cell-based therapies. 2. The study introduces a "docking-while-binding" technique that simultaneously optimizes protein-protein and protein-ligand interactions. This method allows for the de novo creation of ligand binding pockets directly at the protein-protein interface, enabling the design of homotrimers, heterodimers, and heterotrimers. 3. The designed amantadine-regulated protein oligomers were validated in cellular and animal models, demonstrating their ability to control gene expression, protein localization, and reversible condensate formation. Notably, the system achieved noninvasive, dose-dependent control of gene expression in mice through oral administration of amantadine. 4. The compact size of the protein components (~65 amino acids) and the use of an orally bioavailable small molecule make this system highly suitable for translational applications. The approach opens new avenues for developing next-generation chemically inducible protein assembly tools. 5. The study highlights the potential for further optimization using deep learning models and the incorporation of additional ligands to enhance sensitivity. This work represents a significant advancement in the field of chemogenetics, providing a versatile toolkit for manipulating complex biological processes. 📜Paper: science.org/doi/10.1126/scie… #ProteinDesign #Chemogenetics #SyntheticBiology #Biotechnology #GeneRegulation