Tumor suppressor p53,as a transcription factor,regulates the expression of a series of genes to prevent cells from becoming cancerous.It was reported that p53 is linked to more than 50%of human cancers.With marginal stabilities,it was commonly admitted that wild-type(WT)p53 and some mutants p53 are liable to unfold and aggregate by a prion-like behavior.The p53 aggregation is related to loss-of-function(LoF),dominant-negative(DN)and gain-of-function(GoF)effects of p53,leading to diverse cancer consequences.R175H and R273H are two hot-spot cancer mutants occurring in p53 DNA binding domain.Recent experimental studies have suggested that the two mutants R175H and R273H are easier to aggregate than WT p53.However,the molecular mechanism underlying the higher aggregation propensities remains elusive.Here,we investigated the aggregation propensities of the two mutants R175H and R273H by performing extensive all-atom molecular dynamics(MD)simulations.We found that the two mutants both exhibited larger root mean square deviation relative to their initial conformation,larger hydrophobic surface areas and radius of gyration,and higher loop flexibilities than WT p53.These physical and conformational properties are consistent with structural features of pre-amyloidogenic molten-globule(MG)states which own higher propensities toward aggregation.Moreover,in mutant R175H,the distance between Zn2+ion and the S atom of the coordinated residue C238 increased significantly,which facilitates the dissociation of Zn2+ion from p53 and further aggregation.In addition,our simulation data indicated the loss of Zn2+ion in mutant R175H is likely initiated from residue C238.These results provide mechanistic insights into high aggregation propensities of the two hot-spot mutants R175H and R273H with respect to WT p53.