Theoretical Study Of The Effect Of The R823W Mutation On The Interaction Of The ANKS3- ANKS6

Among the inherited renal cystic disease, the autosomal dominant polycystic kidney disease(ADPKD) is the most common one. The Cy mutation is found to be a missense mutation in the ANKS6 gene, encoding the anchor protein and the sterile alpha motif(SAM) domain, which includes the ANKS6 area. The sterile alpha mot if(SAM) domain is a protein-protein interaction domain. Prior works suggested that the ANKS6 can bind to ANKS3, forming a ANKS3-ANKS6 bipolymer. The Cy mutation happens in the SAM domain and accounts for the exchange of a highly conserved arginine residue with a tryptophan residue at amino acid R823-ANKS6(R823W).Although the inherited renal cystic disease is the result of the R823 W point mutation in the SAM domain of the protein ANKS6, the molecular details about the effect of the mutation on the interaction of the ANKS3-ANKS6 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 on the wild type(PDB ID: 4NL9) and mutation to explore the structural and dynamic effects of the R823 W point mutation on the complex ANKS3-ANKS6.According to the hydrogen bonds analysis, the higher hydrogen occupancy rate of the WT than the mutant means that the wide type is more stable than the mutant. Based on the cluster analysis, the mutant generates more clusters, each of which has more structures, which means less stable. According to the correlation analysis, the mutant has higher correlation than the WT, indicating the R823W-ANKS6 point mutation changes the structure of the complex and decreases the stability of the ensemble complex. By the results of the principal component analysis we learn that the wild type has the more stable structure and the lower energy than the mutant. From the MM-PBSA binding free energy calculation, the higher energy of the mutant than WT indicates the WT is more stable than the mutant and the R823W-ANKS6 mutation affect the interaction of the ANKS3-ANKS6.On the basis of the above analysis, we can deduce that the R823 W point mutation not only disrupts the structure of the ANKS6 –ANKS3, reducing its stability but also negatively affects the interaction of the ANKS3-ANKS6, which is agreed to the previous experiment result. Our study not only helps us better understand the effect of the R823 W mutation on the ANKS3-ANKS6, but also provide a theoretical basis for the research and treatment of the autosomal dominant polycystic kidney disease.