Roles of computational modelling in understanding p53 structure, biology, and its therapeutic targeting

The multi-faceted role of the transcription factor p53 is key to numerous biological processes, including the suppression of tumours. The availability since the 1990s of a richness of biophysical data aimed at understanding its structure-function relationships has enabled the application of a variety of atomistic computational modelling techniques towards the establishment of mechanistic models. Together they have provided deep insights into the structure, mechanics, energetics, and dynamics of p53. In parallel, the observation that mutations in p53 or changes in its associated pathways characterise several human cancers has resulted in a race to develop therapeutic modulators of p53, some of which have entered clinical trials. This review describes how computational modelling has played key roles in understanding structural-dynamic aspects of p53, the development of hypotheses particularly in domains that are beyond current experimental investigations, and towards the successful exploitation of the models for the development of therapeutic molecules to activate p53.