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使用AlphaFold3和分子动力学模拟研究148种错义突变导致p53功能障碍的结构机制

Investigation of Structural Mechanisms Underlying p53 Dysfunction Caused by 148 Missense Mutations Using AlphaFold3 and Molecular Dynamics Simulations.

作者信息

Rustamov Kh R, Razzokov J I, Baev A Y

机构信息

Laboratory of Experimental Biophysics, Center for Advanced Technologies, Tashkent 100174, Uzbekistan.

Institute of Fundamental and Applied Research, National Research University TIIAME, Kori Niyoziy 39, Tashkent 100000, Uzbekistan.

出版信息

J Chem Inf Model. 2025 Jun 23;65(12):6322-6330. doi: 10.1021/acs.jcim.5c00580. Epub 2025 Jun 4.

DOI:10.1021/acs.jcim.5c00580
PMID:40464633
Abstract

Tumor protein p53 (TP53) is a crucial regulator of genomic integrity, frequently mutated in more than half of all human cancers. These mutations predominantly target the DNA-binding domain (DBD), impairing p53's interaction with DNA and its tumor-suppressive functions. To elucidate the structural and functional consequences of p53 mutations, we investigated 148 missense variants located within its DNA-binding interface using cutting-edge computational approaches. We employed AlphaFold3 (AF3) to predict p53-DNA complex structures, integrating these predictions with molecular dynamics (MD) and force-guided pulling simulations to assess mutation-induced changes in structural stability and DNA-binding properties. Moreover, we compared the results of our study with experimental in vitro enrichment scores (RFS) and Combined Annotation Dependent Depletion (CADD). We identified a moderate negative correlation between plDDT and the pathogenicity of mutant variants, suggesting that mutations causing more significant alterations in the protein tertiary structure have a greater negative impact on cellular function. Moreover, we identified two possible structural mechanisms through which mutations can impair the p53 functionality. Specifically, some mutations, such as R248P and N239S, reduce the binding affinity of the p53-DNA complex, whereas others, such as C238Y and P278R, enhance affinity but compromise the structural stability of the complex. Furthermore, we uncovered mutations with potential rescuing effects, such as E285A and M243T, which preserved structural stability and enhanced the DNA-binding ability. Our findings provide a comprehensive framework for understanding the molecular mechanisms underlying p53 mutations and their role in cancer pathogenesis. This study highlights the value of integrative computational approaches in investigating protein-nucleic acid interactions, providing critical insights that can guide the development of therapeutic strategies targeting p53 mutations.

摘要

肿瘤蛋白p53(TP53)是基因组完整性的关键调节因子,在超过一半的人类癌症中经常发生突变。这些突变主要靶向DNA结合结构域(DBD),损害p53与DNA的相互作用及其肿瘤抑制功能。为了阐明p53突变的结构和功能后果,我们使用前沿计算方法研究了位于其DNA结合界面内的148个错义变体。我们采用AlphaFold3(AF3)预测p53-DNA复合物结构,将这些预测与分子动力学(MD)和力引导拉伸模拟相结合,以评估突变引起的结构稳定性和DNA结合特性变化。此外,我们将研究结果与实验性体外富集分数(RFS)和联合注释依赖缺失(CADD)进行了比较。我们发现plDDT与突变变体的致病性之间存在适度的负相关,这表明在蛋白质三级结构中引起更显著改变的突变对细胞功能有更大的负面影响。此外,我们确定了两种可能的结构机制,通过这些机制突变会损害p53的功能。具体而言,一些突变,如R248P和N239S,会降低p53-DNA复合物的结合亲和力,而其他突变,如C238Y和P278R,会增强亲和力,但会损害复合物的结构稳定性。此外,我们发现了具有潜在挽救作用的突变,如E285A和M243T,它们保留了结构稳定性并增强了DNA结合能力。我们的研究结果为理解p53突变的分子机制及其在癌症发病机制中的作用提供了一个全面的框架。这项研究强调了综合计算方法在研究蛋白质-核酸相互作用中的价值,提供了关键见解,可指导针对p53突变的治疗策略的开发。

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