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<p>Enzymes are powerful and sustainable catalysts, but their widespread application is limited by the difficulty of identifying functional starting points for optimization, creating a major bottleneck in early- stage biocatalyst discovery. Designing libraries of such starting enzymes remains particularly challenging. Here, we use the GenSLM protein language model to generate novel <i>β</i>-subunit of tryptophan synthase (TrpB) enzymes that express in <i>Escherichia coli</i> and are both stable and catalytically active. Many generated TrpBs also display significant substrate promiscuity, outperforming their natural counterparts on non-native substrates. Some even surpass laboratory-evolved TrpBs. Comparison of the most-active and most-promiscuous generated TrpB to its closest natural homolog confirms that the enhanced versatility is absent from the natural enzyme, highlighting the creative potential of generative models. These results demonstrate that the generated TrpBs not only preserve natural structure and function but also acquire non-natural properties, establishing generative models as powerful tools for biocatalyst discovery and engineering.</p>

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Sequence-based generative AI design of versatile tryptophan synthases

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年1月14日

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  • Théophile Lambert,
  • Amin Tavakoli,
  • Gautham Dharuman,
  • Jason Yang,
  • Vignesh Bhethanabotla,
  • Sukhvinder Kaur,
  • Matthew Hill,
  • Arvind Ramanathan,
  • Anima Anandkumar,
  • Frances H. Arnold

摘要

Enzymes are powerful and sustainable catalysts, but their widespread application is limited by the difficulty of identifying functional starting points for optimization, creating a major bottleneck in early- stage biocatalyst discovery. Designing libraries of such starting enzymes remains particularly challenging. Here, we use the GenSLM protein language model to generate novel β-subunit of tryptophan synthase (TrpB) enzymes that express in Escherichia coli and are both stable and catalytically active. Many generated TrpBs also display significant substrate promiscuity, outperforming their natural counterparts on non-native substrates. Some even surpass laboratory-evolved TrpBs. Comparison of the most-active and most-promiscuous generated TrpB to its closest natural homolog confirms that the enhanced versatility is absent from the natural enzyme, highlighting the creative potential of generative models. These results demonstrate that the generated TrpBs not only preserve natural structure and function but also acquire non-natural properties, establishing generative models as powerful tools for biocatalyst discovery and engineering.