Y220C突变体影响p53C蛋白质构象转换的分子动力学模拟

p53是迄今发现突变频率最高的一种肿瘤抑制蛋白质，突变会导致p53抑癌功能丧失并诱导癌症的发生。绝大多数的突变发生在p53的核心DNA结合区域（p53C），其中Y220C是研究较多的一种突变体。虽然已有研究表明该突变能够降低p53C的结构稳定性，但其影响p53C构象转换的分子机制尚不清晰。本文利用分子动力学（MD）模拟方法研究了p53C突变体Y220C（p53C-Y220C）的结构变化，发现Y220C突变主要影响Y220C cluster区域（包括残基138-164和215-238），且Y220C突变减少了Y220C cluster的β-折叠含量。进一步分析发现，Y220C突变不仅直接破坏突变氨基酸与周围氨基酸Leu145和Thr155之间的氢键，而且降低了Y220C cluster区域的折叠片S3和S8之间的氢键数量，使Y220C突变所形成的亲水性空腔变大，加速了水分子进入该蛋白质内部，并最终导致了p53C-Y220C变性。MD模拟结果揭示了Y220C突变影响p53C结构转换的分子机制，该研究对p53C-Y220C突变体高效稳定剂的筛选和设计具有重要意义。

Effect of Y220C Mutant on the Conformational Transition of p53C Probed by Molecular Dynamics Simulation

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.