1544-De Novo Design of Fluorophore-Binding Proteins

Researchers used computational protein design and machine learning to create a new class of small proteins, called Novotags, that specifically bind to high-performance synthetic dyes. These engineered proteins combine the genetic targetability of traditional fluorescent proteins with the superior brightness and stability of chemical fluorophores. By developing versions that bind distinct dyes across the visible spectrum, the team enabled multiplexed imaging, allowing multiple cellular components to be visualized simultaneously with high resolution. The study further introduced covalent binders for permanent labeling and split-protein systems that act as sensors for protein-protein interactions. Additionally, the scientists demonstrated that the fluorescence lifetime of these dyes can be adjusted through protein engineering, providing an extra dimension for complex biological tracking. This integrated approach significantly expands the toolkit available for super-resolution microscopy and live-cell analysis.

References:

• Tran L, Klein S, Juergens D, et al. De novo design of orthogonal far-red, orange, and green fluorophore-binding proteins for multiplexed imaging[J]. Science, 2026: eaeb0822.