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Unveiling the State Transition Mechanisms of Ras Proteins through Enhanced Sampling and QM/MM Simulations

Fangchen Hu1, Yiqiu Wang1, Juan Zeng2

  • 1School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China.

The Journal of Physical Chemistry. B
|February 7, 2024
PubMed

Insights

Researchers simulated the HRasGTP complex

Area of Science:

  • Molecular Biology
  • Biochemistry
  • Computational Biology

Background:

  • RasGTP complexes exist in active (State 2) and inactive (State 1) forms.
  • These states regulate cellular functions through transitions.
  • The mechanisms of RasGTP state transitions remain unclear.

Purpose of the Study:

  • To investigate the energetics of HRasGTP state transitions, particularly from State 2 to State 1.
  • To elucidate the conformational changes involved in HRasGTP state transitions.
  • To provide insights into KRas and NRas state transitions.

Main Methods:

  • Multiscale quantum mechanics/molecular mechanics (QM/MM) simulations.
  • Enhanced sampling molecular dynamics (MD) methods.
  • Construction of 2D free energy landscapes.

Main Results:

  • Characterized the energetics of stable states in HRasGTP transitions.
  • Mapped conformational changes from State 2 to State 1.
  • Explored conformational changes during GTP hydrolysis from intermediate to product states.

Conclusions:

  • Detailed free energy landscapes reveal HRasGTP conformational dynamics.
  • Simulation results offer a reference for understanding Ras family protein dynamics.
  • Elucidated key aspects of HRasGTP state transitions and GTP hydrolysis.

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