The energetics of the acetylation switch in p53-mediated transcriptional activation

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• p53 protein is a crucial tumor suppressor involved in regulating gene expression.
• The interaction between p53 and its coactivator CBP is vital for p53-mediated transcriptional activity.
• Acetylation of p53, particularly at K382, is known to modulate its function.

Purpose of the Study:

• To investigate the energetic contribution of K382 acetylation to the p53-CBP binding complex.
• To understand how acetylation at K382 influences the binding affinity and selectivity of p53 to the CBP bromodomain.
• To elucidate the molecular mechanisms underlying p53-CBP interaction modulation by post-translational modifications.

Main Methods:

• Molecular dynamics simulations of p53-CBP complex and a derived octapeptide.
• Free Energy Perturbation (FEP) simulations to quantify binding energy changes.
• MM-GBSA (Molecular Mechanics with Generalized Born Surface Area) analysis for residue contribution to binding energy.

Main Results:

• Acetylation of K382 in the free peptide does not significantly alter its preferred conformation for CBP binding.
• FEP simulations revealed that the acetyl group at K382 contributes approximately 4.8 kcal/mol to the binding energy of the p53-CBP complex.
• MM-GBSA analysis corroborated FEP results, identifying specific residue contributions and explaining binding selectivity.

Conclusions:

• K382 acetylation is a key regulatory switch that significantly impacts the binding energetics of p53 to the CBP bromodomain.
• The acetyl group at K382 plays a substantial role in the affinity and selectivity of the p53-CBP interaction.
• Understanding these molecular interactions provides insights into targeted therapeutic strategies for diseases involving p53 dysfunction.