Redesign selective protein binders using contrastive decoding

MotivationFixed-backbone sequence design methods such as ProteinMPNN operate on backbone coordinates alone and cannot represent target side-chains at the binding interface. Their decoding algorithm also lacks a mechanism to balance binding affinity and folding stability or to improve selectivity against structurally similar off-targets. These gaps limit the computational design of protein binders with high affinity and specificity. ResultsWe present RedNet, a multiscale graph neural network that encodes side-chain information of the binding target. We further develop a contrastive decoding algorithm, motivated by the thermodynamic decomposition of binding free energy, that addresses two objectives: (1) balancing binding affinity and folding stability, and (2) improving selectivity against structurally similar off-targets. RedNet reaches 43% native sequence recovery on heterodimers, compared with 37% for ProteinMPNN and 33% for ESM-IF. With contrastive decoding, it matches native-sequence co-folding success (68%) on high-confidence AlphaFold3 targets, exceeding ProteinMPNN (59%) and ESM-IF (61%). On a new benchmark of structurally similar on-/off-target pairs, RedNet with contrastive decoding reaches 64.8% energetic selectivity, ahead of PiFold (55.6%), ProteinMPNN (53.7%), and ESM-IF (53.7%). AvailabilitySource code and datasets are released at https://github.com/zw2x/rednet_public. Contactjinbo.xu@gmail.com