ProteoCraft: Protein Design as Proposal-Verification Search

Fang Wu; Hongbin Lin; Bingchen Duan; Yuchen Wang; Li Erran Li; Yanjie Huang; Mingxuan Cao; Yijun Ma; Yunxiang Mo; Yanchao Li; Kuan Pang; Juangui Xu; Hanqun Cao; Dongwei Jiang; Xinyue Xu; Xiangru Tang; Zehong Wang; Jian Ma; Kejun Ying; Guanlue Li; Mingran Cao; Fanjin Wang; Tianfan Fu; Shuangjia Zheng; Yao Shu; Jure Leskovec; Yejin Choi

arXiv · 2611.03963

ProteoCraft: Protein Design as Proposal-Verification Search

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Abstract

Protein-protein interactions underpin nearly all biological processes. Yet, designing proteins with desired interactions remains challenging due to the structural complexity governing molecular recognition. This study views protein design as a search optimization problem over a combinatorial sequence space under expensive structural evaluation. Toward this goal, we introduce a novel tree-based search framework, ProteoCraft, that employs approximate structural gradients from diffusion-based structure predictors as effective proposal policies to specify where the search should explore. Complete no-gradient inference of folding models separately assigns values to the resulting sequences, determining what is good. ProteoCraft allocates this verification budget through a coarse-to-fine paradigm: multi-site edits first explore distinct sequence basins, then verified promising states undergo strict single-site refinement. Across fourteen de novo binder-design settings spanning eight target proteins, five immune-relevant TCR-facing targets, and four localized CDR redesign tasks, ProteoCraft improves design quality and high-confidence yield. These improvements persist under independent AF2-IG and Rosetta-based interface evaluation. Prospective experimental validation further yielded an 82.9% binding hit rate for PD-L1 miniproteins, with a best measured KD of 0.879 nM, and confirmed binding of designed IFNAR2 VHH. Our code is available at https://github.com/smiles724/ProteoCraft_v1.

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Fang Wu, Hongbin Lin, Bingchen Duan, Yuchen Wang, Li Erran Li, Yanjie Huang, Mingxuan Cao, Yijun Ma, Yunxiang Mo, Yanchao Li, Kuan Pang, Juangui Xu, Hanqun Cao, Dongwei Jiang, Xinyue Xu, Xiangru Tang, Zehong Wang, Jian Ma, Kejun Ying, Guanlue Li, Mingran Cao, Fanjin Wang, Tianfan Fu, Shuangjia Zheng, Yao Shu, Jure Leskovec, Yejin Choi. 2026-11-02. ProteoCraft: Protein Design as Proposal-Verification Search. https://arxiv.org/abs/2611.03963

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