Ser133 phosphate-KIX interactions in the CREB-CBP complex: an ab initio molecular dynamics study

Area of Science:

• Biochemistry
• Molecular Biology
• Computational Chemistry

Background:

• Cyclic AMP response element binding protein (CREB) activates transcription by binding to CREB-binding protein (CBP).
• The interaction between phosphorylated CREB (pSer133) and CBP residues (Tyr658, Lys662) is critical for complex stability.
• Previous models emphasized electrostatic interactions in the CREB-CBP complex.

Discussion:

• This study employs ab initio methods to analyze the dynamics and energetics of a hydrated CREB-CBP complex model.
• Investigates the roles of electrostatics, hydrogen bonding, and hydration in complex formation.
• Examines the electronic charge density reorganization during complex assembly.

Key Insights:

• A previously unrecognized low-barrier hydrogen bond between pSer133 and Lys662 significantly stabilizes the CREB-CBP complex, alongside electrostatics.
• Hydration is essential for stabilizing the charged phosphate group of pSer133.
• Complex formation involves substantial reorganization of electronic charge density.

Outlook:

• Further research can explore the implications of these findings for drug design targeting the CREB-CBP interaction.
• Experimental validation of the proposed low-barrier hydrogen bond and hydration effects is warranted.
• This work provides a foundation for understanding other protein-protein interactions involving phosphorylated residues.