Journal: Angew Chem Int Ed Engl / Year: 2026 Title: De Novo Design of a Protein Binder to Probe Gas Channel and Enhance the Oxygen Tolerance of [NiFe]-Hydrogenase. Authors: Xuan Sun / Qi Xiao / Nan Zhang / Wenjin Li / Hang Luo / Yanxin Gao / Leyan Zhang / Yilin Fan / Peiyu Jiang / Yucen Huang / Geng Wu / Liyun Zhang / Abstract: [NiFe]-Hydrogenases display remarkable catalytic efficiency for H production and oxidation but are sensitive to O, which severely restricts their biotechnological applications. The identities and ...[NiFe]-Hydrogenases display remarkable catalytic efficiency for H production and oxidation but are sensitive to O, which severely restricts their biotechnological applications. The identities and functional relevance of gas channels leading to the buried [NiFe] active site remain elusive, hindering rational enzyme engineering. Here, we introduce an artificial intelligence-guided de novo protein binder design strategy to map hydrophobic O diffusion pathways in Escherichia coli hydrogenase-2 (Hyd-2). By integrating RFdiffusion, ProteinMPNN, and AlphaFold, ∼100,000 candidate binders were computationally screened, yielding two high-affinity binders, L1 and L2. Biophysical and electrochemical analyses show that L1 selectively occludes the primary O ingress channel, enhancing the enzyme's oxygen tolerance by more than threefold, whereas L2, which targets another putative channel, has a negligible effect, indicating that this pathway contributes minimally to O ingress under the tested conditions. Furthermore, we determined the L1-Hyd-2 complex structure by cryo-electron microscopy and revealed the key interaction residues and interface conformation. Integrated structural and computational analyses provide mechanistic insights into the system's oxygen tolerance and high-affinity L1-Hyd-2 interaction. All findings provide the first direct experimental evidence for hierarchical O diffusion channels in [NiFe]-hydrogenases and establish binder-mediated channel occlusion as a generalizable, mutation-free strategy for elucidating and modulating gas transport in metalloenzymes.
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