Latent generative search unlocks de novo design of untapped biomolecular interactions at scale.

ABSTRACT: De novo protein design has advanced rapidly, yet designing binders to polar, solvent-exposed epitopes and small, flexible ligands remains challenging. Such hydrated surfaces and flexible molecules, including carbohydrates, provide few of the hydrophobic contacts favoured by current methods and have largely resisted de novo binders. To address this challenge, here we introduce latent generative search for binder design, a novel framework that uses reward-guided search at inference time to steer the Proteína-Complexa generative model. The model codesigns sequence and structure - generating them together in a continuous latent space - and thereby removes the inverse-folding step on which current methods rely. In a screen of more than one million designs by multiplexed phage display, latent ge

SUBMITTER: Didi K 

PROVIDER: S-EPMC13596280 | biostudies-literature | 2026 Sep

REPOSITORIES: biostudies-literature