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How and when disulfide bonds form in proteins relative to the stage of their folding is a fundamental question in cell biology. Two models describe this relationship: the folded precursor model, in which a nascent structure forms before disulfides do, and the quasi-stochastic model, where disulfides form prior to folding. Here we investigated oxidative folding of three structurally diverse substrates, β2-microglobulin, prolactin, and the disintegrin domain of ADAM metallopeptidase domain 10 (ADAM10), to understand how these mechanisms apply in a cellular context. We used a eukaryotic cell-free translation system in which we could identify disulfide isomers in stalled translation intermediates to characterize the timing of disulfide formation relative to translocation into the endoplasmic reticulum and the presence of non-native disulfides. Our results indicate that in a domain lacking secondary structure, disulfides form before conformational folding through a process prone to nonnative disulfide formation, whereas in proteins with defined secondary structure, native disulfide formation occurs after partial folding. These findings reveal that the nascent protein structure promotes correct disulfide formation during cotranslational folding.

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Hydrogen spillover-based binary (HSBB) catalysts have attracted more and more attention in recent years because of their unique reaction mechanism, different from traditional single-component catalysts. In this paper, using density functional theory for the screening of materials, we find 11 candidates with excellent hydrogen evolution reaction (HER) performance under acidic conditions. Among them, Pt1Ir1-MoS2 has been successfully synthesized and verified through experiment to have exhibited the outstanding catalytic performance as predicted. Detailed analysis of these HSBB catalysts reveals the key role of hydrogen spillover toward efficient water splitting, paving the way for the discovery of widely applicable materials and a feedback loop that delivers materials as designed. Greatly increasing the number of known HSBB catalysts, the current study not only demonstrates the accuracy of our screening of materials but also provides a novel paradigm for accelerating the development of materials and reducing costs.