A Hybrid All-Atom Structure-Based Model for Protein Folding and Large Scale Conformational Transitions

Area of Science:

• Computational Biology
• Biophysics
• Structural Biology

Background:

• Structure-based models are effective for protein folding energy landscapes.
• Existing models struggle with unbiased descriptions of local interactions during conformational changes.
• Studying complex protein rearrangements requires efficient and transferable models.

Purpose of the Study:

• To develop and validate a new all-atom model for simulating protein conformational transitions.
• To accurately capture both local and long-range interactions in proteins.
• To investigate the mechanisms of protein folding and kinase activation.

Main Methods:

• Developed an all-atom model combining classical force fields for local interactions and structure-based potentials for long-range interactions.
• Validated the model using simulations of protein folding for the villin headpiece and SH3 domain.
• Applied the model to study the activation mechanism of the c-Src kinase catalytic domain.

Main Results:

• The model successfully simulated protein folding reactions and characterized transition states.
• Simulations of c-Src kinase revealed a conformational rearrangement involving a loop and an alpha helix.
• A stable intermediate state was identified in the free energy landscape, suggesting a loop-opening mechanism.

Conclusions:

• The proposed all-atom model offers an accurate and computationally efficient approach for studying protein conformational transitions.
• The model's ability to capture local and long-range interactions makes it suitable for large protein systems.
• This method provides insights into the mechanisms of protein dynamics and activation.