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Path Ensembles for Pin1-Catalyzed Cis-Trans Isomerization of a Substrate Calculated by Weighted Ensemble Simulations.

Kei Moritsugu1, Norifumi Yamamoto2, Yasushige Yonezawa3

  • 1Graduate School of Medical Life Science, Yokohama City University, 1-7-29 Suehirocho, Tsurumi, Yokohama, Kanagawa 230-0045, Japan.

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Pin1 enzyme catalysis of cis-trans isomerization involves structural dynamics essential for its function. Weighted ensemble simulations reveal the molecular mechanism, identifying key residues and Ser154

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Computational Chemistry

Background:

  • Pin1 enzyme catalyzes peptidyl-prolyl bond isomerization between cis and trans forms.
  • Understanding the structural dynamics of this isomerization is crucial for elucidating enzyme catalysis mechanisms.

Purpose of the Study:

  • To apply weighted ensemble (WE) simulations to comprehensively study the Pin1-catalyzed isomerization process.
  • To calculate rate constants and analyze the free energy landscape of cis-trans isomerization.
  • To elucidate the molecular mechanism, including the role of specific residues and transition states.

Main Methods:

  • Weighted ensemble (WE) simulation method.
  • Calculation of rate constants for cis-to-trans and trans-to-cis isomerization.
  • Free energy landscape analysis.
  • Committor-like analysis to determine transition state shifts.
  • WE and free energy calculations for a Ser154Ala (S154A) mutant.

Main Results:

  • Rate constants for isomerization were calculated on submicrosecond timescales.
  • The cis form was found to be slightly less energetically favorable than the trans form.
  • The transition state shifted towards the trans form (ω ≈ 110°) compared to the isolated substrate (ω ≈ 90°).
  • Key residues (His59/His157, Lys63/Arg68/Arg69) were identified to anchor the substrate.
  • Serine 154 was identified as a critical residue facilitating isomerization by relaying hydrogen bonds.
  • The S154A mutation resulted in slower isomerization and an increased free energy barrier.

Conclusions:

  • WE simulations are effective for sampling reaction pathways and unraveling enzyme mechanisms.
  • The study clarifies the molecular mechanism of Pin1-catalyzed isomerization, highlighting the roles of specific residues and the transition state shift.
  • Ser154 plays a crucial role in driving the isomerization process.