Computational study of the "DFG-flip" conformational transition in c-Abl and c-Src tyrosine kinases

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• Protein tyrosine kinases (PTKs) are essential regulators of cellular signaling pathways.
• PTK activity is tightly controlled, with the Asp-Phe-Gly (DFG) motif conformation influencing kinase activity.
• The DFG motif can transition between active (DFG-in) and inactive (DFG-out) states.

Purpose of the Study:

• To computationally determine the reaction pathway and thermodynamic factors governing DFG motif conformational transitions in c-Abl and c-Src kinases.
• To compare the DFG motif conformational dynamics between c-Abl and c-Src.

Main Methods:

• String method with swarms-of-trajectories to identify reaction pathways.
• Umbrella sampling calculations to characterize free energy landscapes.
• Analysis of DFG motif conformational transitions in c-Abl and c-Src.

Main Results:

• The DFG-out conformation is thermodynamically more favorable for c-Abl than for c-Src.
• Protonation state of the aspartate residue in the DFG motif significantly impacts the in/out transition in c-Abl.
• Local structural differences in c-Src reduce the impact of aspartate protonation on the DFG motif transition.

Conclusions:

• The study elucidates the distinct conformational dynamics of the DFG motif in c-Abl and c-Src.
• Protonation state of key residues plays a critical role in regulating kinase activity, particularly in c-Abl.
• These findings contribute to understanding kinase regulation and inform the design of targeted inhibitors.