Influence of the R823W mutation on the interaction of the ANKS6- ANKS3: Insights from molecular dynamics simulation and free energy analysis

The sterile alpha motif (SAM) domain of the protein ANKS6, a protein-protein interaction domain, is responsible for autosomal dominant polycystic kidney disease (ADPKD). Although the disease is the result of the R823W point mutation in the SAM domain of the protein ANKS6, the molecular details is still unclear. We applied molecular dynamics (MD) simulations, principal component analysis (PCA) and the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) binding free energy calculation to explore the structural and dynamic effects of the R823W point mutation on the complex ANKS6-ANKS3 (PDB ID: 4NL9) in comparison to the wild proteins. The energetic analysis presents that the wide type has a more stable structure than the mutant. The R823W point mutation not only disrupts the structure of the ANKS6 SAM domain but also negatively affects the interaction of the ANKS6-ANKS3. These results further clarify the previous experiments to understand the ANKS6-ANKS3 interaction comprehensively. In summary, this study would provide useful suggestions to understand the interaction of these proteins and their fatal action on mediating kidney function.

蛋白质ANKS6的无菌α基序（SAM结构域）作为一类蛋白质相互作用结构域，与常染色体显性遗传性多囊肾病（ADPKD）的致病过程相关。尽管该疾病的根源为ANKS6蛋白SAM结构域内的R823W点突变，但其具体分子细节仍未明确。本研究采用分子动力学（MD）模拟、主成分分析（PCA）以及分子力学-泊松玻尔兹曼表面积（MM-PBSA）结合自由能计算方法，对比野生型蛋白与突变体，探究R823W点突变对ANKS6-ANKS3复合物（蛋白质数据库编号：4NL9）的结构与动态特性产生的影响。能量分析结果显示，野生型复合物的结构稳定性优于突变体。R823W点突变不仅破坏了ANKS6 SAM结构域的固有构象，还对ANKS6与ANKS3的相互作用产生负面影响。上述结果进一步阐释了既往实验结论，有助于全面理解ANKS6与ANKS3的相互作用机制。综上，本研究可为阐明这两种蛋白质的相互作用及其在调控肾脏功能中的关键致病作用提供有价值的参考依据。