Conformational Heterogeneity and Frustration of the Tumor Suppressor p53 as Tuned by Punctual Mutations

The conformational heterogeneity of the p53 tumor suppressor, the wild-type (p53wt) and mutated forms, was investigated by a computational approach, including the modeling and all atoms of the molecular dynamics (MD) simulations. Four different punctual mutations (p53R175H, p53R248Q, p53R273H, and p53R282W) which are known to affect the DNA binding and belong to the most frequent hot-spot mutations in human cancers, were taken into consideration. The MD trajectories of the wild-type and mutated p53 forms were analyzed by essential dynamics to extract the relevant collective motions and by the frustration method to evaluate the degeneracy of the energy landscape. We found that p53 is characterized by wide collective motions and its energy landscape exhibits a rather high frustration level, especially in the regions involved in the binding to physiological ligands. Punctual mutations give rise to a modulation of both the collective motions and the frustration of p53, with different effects depending on the mutation. The regions of p53wt and of the mutated forms characterized by a high frustration level are also largely involved in the collective motions. Such a correlation is discussed also in connection with the intrinsic disordered character of p53 and with its central functional role.