Mechanisms of p53 core tetramer stability mediated by multi-interface interactions: A molecular dynamics study

Area of Science:

• Molecular Biology
• Biochemistry
• Structural Biology

Background:

• p53 protein acts as a tumor suppressor, crucial for preventing cancer and maintaining genomic stability.
• The p53 tetramer, essential for its function, is assembled through various cooperative interaction interfaces.
• Understanding the stability mechanisms of the p53 tetramer is key to comprehending its role in cancer suppression.

Purpose of the Study:

• To investigate the internal mechanisms governing the stability of the p53 tetramer.
• To elucidate the roles of different interaction interfaces in p53 tetramer formation and stability.
• To identify key residues and interactions contributing to p53 tetramer stability and DNA binding.

Main Methods:

• Utilized all-atom molecular dynamics simulations to analyze p53 tetramer stability.
• Performed independent simulations of dimeric p53 models to understand structural preferences.
• Analyzed interaction energies and hydrogen bonding patterns at critical interfaces.

Main Results:

• The symmetric interface of the p53 tetramer exhibits conserved interactions, while the dimer-dimer interface shows significant flexibility.
• A novel salt bridge was identified at the dimer-dimer interface, substantially contributing to interaction energy.
• p53 demonstrates a DNA binding affinity more than twice that of its protein-protein interactions, driven by five key residues forming hydrogen bonds.

Conclusions:

• The study provides a theoretical basis for the experimental observation of only the symmetric dimeric structure of p53.
• Identified critical regions and residues that enhance the stability of the p53 tetramer's inter-molecular interaction interfaces.
• Highlighted the distinct contributions of various contact surfaces to the overall formation and stability of the p53 tetramer.