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

Abstract

The sterile alpha motif (SAM) domain of the protein ANKS6, a protein–protein interaction domain, is responsible for autosomal dominant polycystic kidney disease. Although the disease is the result of the R823W point mutation in the SAM domain of the protein ANKS6, the molecular details are still unclear. We applied molecular dynamics simulations, the principal component analysis, and the molecular mechanics Poisson–Boltzmann surface area 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 wild 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.