Smyd2 lysine methyltransferase regulates monomethylation of histone and nonhistone lysine residues using S-adenosylmethionine cofactor as the methyl donor. The nonhistone interactors include several tumorigenic targets, including p53. Understanding this interaction would allow the structural principles that underpin Smyd2-mediated p53 methylation to be elucidated. Here, we performed μ-second molecular dynamics (MD) simulations on binary Smyd2-cofactor and ternary Smyd2-cofactor-p53 peptide complexes. We considered both unmethylated and monomethylated p53 peptides (at Lys370 and Lys372). The results indicate that (a) the degree of conformational freedom of the C-terminal domain of Smyd2 is restricted by the presence of the p53 peptide substrate, (b) the Smyd2 C-terminal domain shows distinct dynamic properties when interacting with unmethylated and methylated p53 peptides, and (c) Lys372 methylation confines the p53 peptide conformation, with detectable influence on Lys370 accessibility to the cofactor. These MD results are therefore of relevance for studying the biology of p53 in cancer progression.

中文翻译：

---

Smyd2构象变化响应p53结合：C末端域的作用。

Smyd2赖氨酸甲基转移酶使用S-腺苷甲硫氨酸辅助因子作为甲基供体，调节组蛋白和非组蛋白赖氨酸残基的单甲基化。非组蛋白相互作用物包括几个致瘤靶标，包括p53。了解这种相互作用可以阐明Smyd2介导的p53甲基化基础的结构原理。在这里，我们对二元Smyd2-辅因子和三元Smyd2-辅因子-p53肽复合物进行了μ秒分子动力学（MD）模拟。我们考虑了未甲基化和单甲基化的p53肽（在Lys370和Lys372处）。结果表明（a）Smyd2 C末端结构域的构象自由度受p53肽底物的存在限制，（b）Smyd2 C末端结构域在与未甲基化和甲基化的p53肽相互作用时显示出明显的动态特性，并且（c）Lys372甲基化限制了p53肽的构象，对Lys370辅助因子的可及性产生可检测的影响。因此，这些MD结果对于研究p53在癌症进展中的生物学意义重大。