Designing enzymes for new-to-nature chemistry and non-natural substrates with AlphaProtein Novo
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Creating highly active enzymes for arbitrary reactions is a transformative goal for the molecular sciences 1 . Traditional protein engineering 2,3 is constrained by a reliance on existing natural starting points, which are often challenging to discover. De novo design offers the potential to overcome this by creating enzymes from first principles 4 , but has yet to achieve practically relevant catalytic properties. Here we present AlphaProtein Novo (AP Novo), a machine-learning pipeline that demonstrates, for the first time, that de novo enzyme design can outperform natural sequence mining in addressing challenging chemistry. We used AP Novo to design new-to-nature nitrene transferases to synthesise the pharmacophore piperidine with unprecedented product selectivity, and to create enzymes that degrade the environmental toxin DEHP under conditions that denature natural enzymes. We also obtained state-of-the-art catalytic efficiencies on two well-studied model reactions, and through iterative design and analysis found that key enablers of success were mechanism-inspired metrics based on AlphaFold 3 5 predictions and sequence-ensemble-based scoring of designed backbones. Our results show that de novo design has become a powerful complement to natural enzyme diversity for discovering catalysts for a range of applications.
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Researchers at Google DeepMind used AlphaProtein Novo to design novel enzymes that catalyze unique chemical reactions with non-natural substrates, showcasing AI's potential in synthetic biology and materials science. https://www.biorxiv.org/content/10.64898/2026.10.01.756017v1
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Combine a chemical knowledge, generative modeling, and structure prediction into a pipeline that can design enzymes for new-to-nature chemistry. @zacharywu.bsky.social @alexechu.bsky.social @francesarnold.bsky.social @pushmeet.bsky.social @juewang.bsky.social www.biorxiv.org/content/10.6...
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www.biorxiv.org/content/10.6...
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Designing enzymes for new-to-nature chemistry and non-natural substrates with AlphaProtein Novo https://www.biorxiv.org/content/10.64898/2026.10.01.756017v1
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Designing enzymes for new-to-nature chemistry and non-natural substrates with AlphaProtein Novo https://www.biorxiv.org/content/10.64898/2026.10.01.756017v1
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https://www.biorxiv.org/content/10.64898/2026.10.01.756017v1 https://www.biorxiv.org/content/10.64898/2026.10.01.754751v1 https://github.com/google-deepmind/alphaprotein-novo
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