Skip to main content
eScholarship
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
  • Gilson, Michael
  • et al.
Abstract

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 mu s 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 Delta Delta G 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.

Many UC-authored scholarly publications are freely available on this site because of the UC Academic Senate's Open Access Policy. Let us know how this access is important for you.

Main Content
Current View