Design of a Protein with Improved Thermal Stability by an Evolution-Based Generative Model

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  • Pengfei Tian
  • Adrien Lemaire
  • Fabien Senechal
  • Olivier Habrylo
  • Viviane Antonietti
  • Pascal Sonnet
  • Valerie Lefebvre
  • Marin, Frederikke Isa
  • Robert B. Best
  • Jerome Pelloux
  • Davide Mercadante

Efficient design of functional proteins with higher thermal stability remains challenging especially for highly diverse sequence variants. Considering the evolutionary pressure on protein folds, sequence design optimizing evolutionary fitness could help designing folds with higher stability. Using a generative evolution fitness model trained to capture variation patterns in natural sequences, we designed artificial sequences of a proteinaceous inhibitor of pectin methylesterase enzymes. These inhibitors have considerable industrial interest to avoid phase separation in fruit juice manufacturing or reduce methanol in distillates, averting chromatographic passages triggering unwanted aroma loss. Six out of seven designs with up to 30 % divergence to other inhibitor sequences are functional and two have improved thermal stability. This method can improve protein stability expanding functional protein sequence space, with traits valuable for industrial applications and scientific research.

Original languageEnglish
Article numbere202202711
JournalAngewandte Chemie International Edition
Issue number50
Pages (from-to)1-8
Publication statusPublished - 2022

    Research areas

  • Coevolution, Molecular Dynamics Simulations, Monte Carlo Simulations, Potts Models, Protein Design, PECTIN METHYLESTERASE, SEQUENCE, EPISTASIS

ID: 328020363