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<p>Hydrogen bonds are fundamental chemical interactions that stabilize protein structures, particularly in β sheets, enabling resistance to mechanical stress and environmental extremes. Here, inspired by natural mechanostable proteins with shearing hydrogen bonds, such as titin and silk fibroin, we de novo designed superstable proteins by maximizing hydrogen-bond networks within force-bearing β strands. Using a computational framework combining artificial intelligence-guided structure and sequence design with all-atom molecular dynamics MD simulations, we systematically expanded protein architecture, increasing the number of backbone hydrogen bonds from 4 to 33. The resulting proteins exhibited unfolding forces exceeding 1,000 pN, about 400% stronger than the natural titin immunoglobulin domain, and retained structural integrity after exposure to 150 °C. This molecular-level stability translated directly to macroscopic properties, as demonstrated by the formation of thermally stable hydrogels. Our work introduces a scalable and efficient computational strategy for engineering robust proteins, offering a generalizable approach for the rational design of resilient protein systems for extreme environments.</p><p></p>

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Computational design of superstable proteins through maximized hydrogen bonding

  • 期刊论文

  • 发表日期：

    2025年11月18日

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  • Bin Zheng,
  • Zhuojian Lu,
  • Shangchen Wang,
  • Lichao Liu,
  • Mingjun Ao,
  • Yurui Zhou,
  • Guojing Tang,
  • Ruishi Wang,
  • Yuanhao Liu,
  • Hantian Zhang,
  • Yinying Meng,
  • Jun Qiu,
  • Tianfu Feng,
  • Ziyi Wang,
  • Renming Liu,
  • Yuelong Xiao,
  • Yutong Liu,
  • Ziling Wang,
  • Yifen Huang,
  • Yajun Jiang,
  • Peng Zheng

摘要

Hydrogen bonds are fundamental chemical interactions that stabilize protein structures, particularly in β sheets, enabling resistance to mechanical stress and environmental extremes. Here, inspired by natural mechanostable proteins with shearing hydrogen bonds, such as titin and silk fibroin, we de novo designed superstable proteins by maximizing hydrogen-bond networks within force-bearing β strands. Using a computational framework combining artificial intelligence-guided structure and sequence design with all-atom molecular dynamics MD simulations, we systematically expanded protein architecture, increasing the number of backbone hydrogen bonds from 4 to 33. The resulting proteins exhibited unfolding forces exceeding 1,000 pN, about 400% stronger than the natural titin immunoglobulin domain, and retained structural integrity after exposure to 150 °C. This molecular-level stability translated directly to macroscopic properties, as demonstrated by the formation of thermally stable hydrogels. Our work introduces a scalable and efficient computational strategy for engineering robust proteins, offering a generalizable approach for the rational design of resilient protein systems for extreme environments.