Toward In Situ Dynamics of DNA-Bound Full-Length p53 Tetramer

Area of Science:

• Molecular Biology
• Structural Biology
• Computational Biology

Background:

• p53 is a critical human tumor suppressor, frequently mutated in cancer.
• Restoring p53 function is a key goal for novel cancer therapies.
• Understanding full-length p53 (fl-p53) structure and dynamics is essential for therapeutic development.

Purpose of the Study:

• To generate the first model of the wild-type (WT) full-length p53 tetramer bound to DNA.
• To elucidate the conformational landscape of WT p53 and cancer mutants using molecular dynamics.
• To identify potential therapeutic targets by analyzing p53 dynamics and interactions.

Main Methods:

• Integrative molecular modeling combining crystal structures and computational techniques.
• Microsecond timescale molecular dynamics simulations on the Anton2 supercomputer.
• Markov state model (MSM) framework for analyzing conformational dynamics.

Main Results:

• A detailed model of the DNA-bound fl-p53 tetramer was generated, revealing DNA bending and compact complex formation.
• WT fl-p53 exhibited a unique quaternary DNA-binding domain (DBD) organization not seen in mutants.
• Differential dynamics were observed between inner and outer DBDs, and a cryptic pocket in loop 6 (L6) was identified.

Conclusions:

• The study provides unprecedented insights into the structural dynamics of DNA-bound fl-p53.
• Cancer mutations (Y220C, G245S) alter p53 tetramer organization and dynamics.
• The identified L6 cryptic pocket represents a potential new target for p53-based cancer therapies.