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<p>Existing experimental results indicate potential disparities between cotranslational protein folding in vivo and free folding in vitro, yet the microscopic mechanisms responsible for these differences remain elusive. In this study, we devised a general protein cotranslational folding (GPCTF) simulations framework by modeling the ribosomal exit tunnel and translation process. Utilizing the GPCTF framework, we conducted extensive molecular dynamics simulations on three proteins of varying topologies, generating over 8 milliseconds of total trajectories. When compared to free folding, cotranslational folding enables the nascent peptide to adopt a more helix-rich structure with less nonnative interactions upon expulsion from the ribosomal exit tunnel. Notably, subsequent folding of this structure adheres to the same pathway as free folding, but with different ratios of folding pathways, modulated by the translation speed. This investigation illuminates the pathway regulation mechanism inherent to cotranslational folding and successfully reconciles discrepancies in pre-existing experimental results, offering significant insights into the protein folding process in vivo.</p><p></p>

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Pathway regulation mechanism by cotranslational protein folding

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月1日

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  • Peng Tao,
  • Yi Xiao

摘要

Existing experimental results indicate potential disparities between cotranslational protein folding in vivo and free folding in vitro, yet the microscopic mechanisms responsible for these differences remain elusive. In this study, we devised a general protein cotranslational folding (GPCTF) simulations framework by modeling the ribosomal exit tunnel and translation process. Utilizing the GPCTF framework, we conducted extensive molecular dynamics simulations on three proteins of varying topologies, generating over 8 milliseconds of total trajectories. When compared to free folding, cotranslational folding enables the nascent peptide to adopt a more helix-rich structure with less nonnative interactions upon expulsion from the ribosomal exit tunnel. Notably, subsequent folding of this structure adheres to the same pathway as free folding, but with different ratios of folding pathways, modulated by the translation speed. This investigation illuminates the pathway regulation mechanism inherent to cotranslational folding and successfully reconciles discrepancies in pre-existing experimental results, offering significant insights into the protein folding process in vivo.