Core Viewpoint - The research presents a novel computational method for designing small molecule-regulated protein oligomers, expanding the toolkit for manipulating complex biological processes [2][3]. Group 1: Research Background and Significance - The study focuses on small molecule-regulated protein oligomerization technology, which allows for precise control of biological processes through spatial proximity of proteins [5]. - Despite over 30 years of development, the number of small molecule-responsive oligomerization systems remains limited, primarily restricted to dimerization, which constrains their application in biological processes requiring multiple protein components [5][6]. - There is a growing demand for more diverse small molecule-responsive protein oligomers in cell engineering and therapeutic development [5]. Group 2: Methodology and Innovations - The research introduces a new computational approach that starts from monomeric protein building blocks to design ligand-responsive oligomers, overcoming the limitations of dimerization [6]. - The method employs a "docking-while-binding" strategy to optimize both protein-protein and protein-ligand interactions during the docking process, enabling the creation of ligand binding pockets directly at the protein-protein interface [6]. - The team successfully designed homomeric trimers that respond to the FDA-approved drug amantadine, demonstrating enhanced response capabilities with the design of both single and dual ligand-binding homomeric trimers [6][10]. Group 3: Applications and Potential - Utilizing the inducibility and multivalency of these homomeric trimers, the research team developed transcription activation systems and reversible protein condensation systems, showcasing broad functional applications [7]. - The optimized systems achieved precise spatiotemporal control of protein localization and gene expression, highlighting their potential in biomedical applications [7][10]. - The use of amantadine, which has favorable oral bioavailability, allows for non-invasive, dose-dependent gene expression control in mouse models, emphasizing the system's strong potential for practical applications [7][10].