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Toward De Novo Protein Design from Natural Language
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Toward De Novo Protein Design from Natural Language

Fengyuan Dai, Shiyang You, Yudian Zhu +23 more
September 2025
 ·
bioRxiv
 ·
DOI 
10.1101/2024.08.01.606258
94
%
Reproducible
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This paper passed independent validation.
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It ranks in the top 1% of preprints assessed in Bioengineering this quarter.
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Why this is interesting

By demonstrating that natural language alone programs novel, functionally active proteins without structural templates or domain expertise, this work dismantles protein design's foundational dependency on existing molecules, making biological function directly addressable from conceptual description.

QED claims analysis

Summary

A 16-billion-parameter generative foundation model trained on 1.7 billion synthetic protein-text pairs can translate natural language descriptions directly into diverse, structurally novel, and functionally active proteins—including catalytically active enzymes—by decomposing the language-to-sequence problem through an intermediate structural representation, with experimental validation demonstrating that all four designed proteins spanning distinct functional classes (fluorescent protein, PETase, alcohol dehydrogenase, and H-protein) exhibited activity and one designed enzyme surpassed its natural counterpart by 1.7-fold.

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Main Claim 1 –

Structural intermediate bridges language-to-sequence protein design

Supporting evidence

  • Data and parameter scaling drive language-guided design performance
  • Larger models improve loss, foldability, and language alignment
Main Claim 2 –

Pinal outperforms prior methods in foldability and text alignment

Main Claim 3 –

Pinal designs novel protein folds that express as soluble proteins

Supporting evidence

  • Pinal expands sequence diversity beyond natural evolutionary clusters
Main Claim 4 –

Natural language prompts yield diverse, functional proteins via Pinal

Supporting evidence

  • Pinal designs catalytically active enzymes matching or exceeding natural performance
  • Single prompt yields functional ADHs across multiple subfamilies
  • Pinal-designed H-protein outperforms native within glycine cleavage system

Abstract

Programming biological function—designing bespoke proteins that execute specific tasks on demand—is a foundational goal of molecular engineering. Yet, current protein design paradigms remain fundamentally limited, typically requiring either an existing protein to evolve from, or deep, family-specific expertise to guide the design process. Here we introduce Pinal, a generative model that overcomes this barrier by translating functional descriptions in natural language directly into diverse and active proteins. This capability is built upon a 16-billion-parameter foundation model trained on an unprecedented synthetic corpus of 1.7 billion protein-text pairs, enabling it to ground functional language in the biophysical principles of protein structure. To provide definitive experimental validation, we tasked Pinal with designing four proteins from distinct functional classes: a fluorescent protein, a polyethylene terephthalate hydrolase, an alcohol dehydrogenase, and a metabolic H-protein. Remarkably, all four designs were functionally active and the two Pinal-designed enzymes achieved catalytic turnover for their respective reactions. Notably, the Pinal-designed H-protein even surpassed its natural counterpart, exhibiting 1.7-fold higher performance. Our results establish that natural language can serve as a programmable instruction set for biology, democratizing protein design and shifting the paradigm from the incremental modification of existing molecules to the direct creation of function from a conceptual description.

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