From mutational inactivation to aberrant gain-of-function: Unraveling the structural basis of mutant p53 oncogenic transition

Various evidence has revealed that mutations in p53 exert activities that go beyond simply inactivation of wildtype functions but rather elicits downstream interactions that promote malignancy described as mutant p53 gain-of-function (GOF). Here we report the first account of the dynamics of mutation-induced structural transition of native p53 to an aberrant gain-of-function state, studying the wildtype (WT) and high incidence contact (R273C) and structural (R175H) mutant p53 (mutp53) through molecular dynamics simulation. Result analysis revealed that both mutants exhibited structural distortion and reduced flexibility, indicative of rigidity and kinetic stability. In addition, surface analysis revealed an increase in the accessible surface area in the p53 mutants. This suggests that the GOF transition involves protein unfolding and exposure of buried hydrophobic surface essential for interaction with HSF-1 oncogenic partner and wildtype p63, and p73 homologs. Further validation revealed binding cavities, similar in the mutants but dissimilar to the WT. Taken together, this study complements experimental findings and reveals the interplay between mutation-induced structural distortion, loss of flexibility, rigidity, enhanced stability, protein unfolding and ultimately, exposure of binding surfaces as conformational attributes that characterize mutP53 structure-GOF activities. This insight is, therefore, of great importance as it opens up a novel therapeutic approach toward the structure based targeting of mutP53 oncogenic involvement beyond wildtype inactivation. Furthermore, exposed binding site information obtained from this study can be explored for structure-based design of substances best described as destabilizers to disrupt the GOF interaction of mutp53.