Conserved internal hydration motifs in protein kinases

Area of Science:

• Biochemistry
• Structural Biology
• Computational Biology

Background:

• Protein kinases are crucial enzymes involved in cell signaling.
• Conserved water molecules within protein kinase cores suggest potential functional roles.
• The impact of internal water on kinase stability and function remains largely unexplored.

Purpose of the Study:

• To computationally characterize the hydration of protein kinase catalytic subunits.
• To investigate the distribution, conservation, and dynamics of internal water molecules.
• To assess the role of conserved water in kinase functional states and plasticity.

Main Methods:

• Systematic screening of crystal structures using a simplified hydration model.
• Analysis of water structure, dynamics, and binding affinities in various kinases.
• Computational assessment of water molecule contributions to protein plasticity.

Main Results:

• A significant portion of buried water molecules in kinases are dynamic.
• Dynamic internal water may contribute to kinase conformational changes during activation.
• Conserved water molecules exhibit binding free energy shifts correlated with kinase functional state changes.

Conclusions:

• Internal water molecules play a specific, fine-tuning role in protein plasticity.
• Conserved water molecules are integral to modulating kinase function and conformational dynamics.
• This study underscores the importance of internal solvent in understanding kinase regulation.