The tumor suppressor p53 regulates transcription in response to cellular stress, with mutations in its DNA-binding domain (DBD) found in most human cancers. The L1 loop within the DBD is believed to play a critical role in DNA recognition, yet its conformational dynamics remain poorly understood. Using enhanced molecular dynamics simulations combined with machine learning-derived collective variables, we reveal a novel conformational switch mechanism governing p53's DNA-binding activity. Our analysis identifies two distinct transition pathways between extended (DNA-binding competent) and recessed conformations, each characterized by specific hydrogen bond networks and high energy barriers. We discovered a potential allosteric mechanism regulating the DNA-p53 binding interface that could provide an atomistic basis for gene-specific transcription regulation. This mechanism would explain the prevalence of certain cancer mutations, particularly at residue R282. Finally, we provide a mechanistic rationale for how compounds targeting a reactivation pocket near the L1 loop may restore p53 function by modulating DNA binding kinetics rather than affinity, thereby reconciling previously observed rescue effects.
Acero et al. (Wed,) studied this question.