Xie, Z.; Xu, J.

Motivation: Fixed-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. Results: We 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, itmatchesnative-sequenceco-foldingsuccess(68%)onhigh-confidenceAlphaFold3 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%).