Abstract:

At present, p53 is the tumor suppressor protein with the highest known frequency of mutation. Mutations in p53 will lead to the loss of its anti-cancer function and initiate cancers. The majority of the mutations in p53 are located in its core DNA binding domain (p53C). One of the most frequent mutation in p53C is Y220C. However, the molecular mechanism of the conformational transition of the Y220C mutant of p53C remains unclear, although it is known that the Y220C mutant greatly decreases the stability of p53C. In this study, molecular dynamics (MD) simulations are used to probe the conformational transition of the Y220C mutant of p53C. The Y220C cluster including residues 138-164 and 215-238, which are strongly affected by the mutant, is identified. The Y220C mutant decreases the content of β-sheets in the Y220C cluster. The Y220C mutation not only disrupts the hydrogen bonds between the mutated residue and surrounding residues such as Leu145 and Thr155, but also weakens the hydrogen bonds between S3 and S8 of the Y220C cluster. This causes the volume of the hydrophilic cavity to increase, accelerating water molecule entry into the cavity, which eventually unfolds the protein. The above MD results explain the molecular mechanism of the Y220C mutant in the conformational transition of p53C. These findings will benefit virtual screening and design of novel stabilizers of the mutant Y220C of p53C.

Key words: Cancer, p53, Residue mutation, Conformational transition, Molecular dynamics simulation