BPS2026 – De novo design of protein binders for programmable control of biomolecular condensates

Biocondensates play a crucial role in various biological functions and are increasingly being explored for applications in health sciences and biotechnology. The programmable control of biocondensates presents a promising avenue for engineering new functionalities, as well as for elucidating their physical properties and regulatory mechanisms. In this study, we aim to design protein binders de novo for the programmable control of biomolecular condensates. We combined the two state-of-the-art pipelines, the diffusion model (RFdiffusion) and AlphaFold hallucination (BindCraft), in conjunction with ProteinMPNN and Boltz1/Pyrosetta, to filter and optimize the structural designs of these protein binders. A total of 60 binders are then experimentally characterized and tested both in vitro and in vivo for their ability to interfere with the condensate. Our study highlights the potential of integrating protein design to enable precise manipulation of biocondensates and other biological processes.