Skip to main content
Open Access Publications from the University of California

Ensemble-based computational approach discriminates functional activity of p53 cancer and rescue mutants.

  • Author(s): Demir, Özlem;
  • Baronio, Roberta;
  • Salehi, Faezeh;
  • Wassman, Christopher D;
  • Hall, Linda;
  • Hatfield, G Wesley;
  • Chamberlin, Richard;
  • Kaiser, Peter;
  • Lathrop, Richard H;
  • Amaro, Rommie E
  • et al.

The tumor suppressor protein p53 can lose its function upon single-point missense mutations in the core DNA-binding domain ("cancer mutants"). Activity can be restored by second-site suppressor mutations ("rescue mutants"). This paper relates the functional activity of p53 cancer and rescue mutants to their overall molecular dynamics (MD), without focusing on local structural details. A novel global measure of protein flexibility for the p53 core DNA-binding domain, the number of clusters at a certain RMSD cutoff, was computed by clustering over 0.7 µs of explicitly solvated all-atom MD simulations. For wild-type p53 and a sample of p53 cancer or rescue mutants, the number of clusters was a good predictor of in vivo p53 functional activity in cell-based assays. This number-of-clusters (NOC) metric was strongly correlated (r(2) = 0.77) with reported values of experimentally measured ΔΔG protein thermodynamic stability. Interpreting the number of clusters as a measure of protein flexibility: (i) p53 cancer mutants were more flexible than wild-type protein, (ii) second-site rescue mutations decreased the flexibility of cancer mutants, and (iii) negative controls of non-rescue second-site mutants did not. This new method reflects the overall stability of the p53 core domain and can discriminate which second-site mutations restore activity to p53 cancer mutants.

Main Content
For improved accessibility of PDF content, download the file to your device.
Current View