Prediction of Deleterious nsSNPs Causing CHARGE Syndrome Associated with the CHD7 Protein using Computational Approaches

The Chromo domain helicase DNA binding protein 7 (CHD7) is also known as ATP-dependent helicase CHD7, in humans, the CHD7 gene encodes it. Heterozygous mutations in this protein cause aggregation and has been determined to have an adverse role in causing CHARGE syndrome. Non-synonymous single nucleotide polymorphism (nsSNP) analysis tends to be deleterious of the protein yet to be employed with computational methods though being the highlight for novel investigations. Various computational methods were used to categorize the 201 identified nsSNPs in the catalytic domain of the CHD7 protein (the nsSNPs are observed to have a damaging effect in the catalytic domain). Pathogenicity analysis determined 81 nsSNPs to be pathogenic and further narrowed down to 61 nsSNPs by stability analysis. Based on the structure availability, the two nsSNPs (P2683S and R2702C) were selected and were checked in the computational tools for sequence analysis (pathogenicity analysis, stability analysis, physiochemical property analysis, and conservational analysis) and were determined to have a high impact over the protein molecule. The molecular dynamics simulation and principal component analysis (PCA) were performed to determine the conformational stability and flexibility change of the proteins. Subsequently, a molecular dynamic simulation (MDS) for 100ns was performed to understand the impact of the differences between the native and the mutant structures of the CHD7 protein. The simulation plots disclose very minute changes in patterns of stability, residue fluctuation, structure compactness, and flexibility regarding P2683S and R2702C mutation compared to the native structure. Further, Molecular docking was performed for the native and the mutant structures P2683S and R2702C to study the binding efficacy of the drugs Methyltestosterone and Estradiol resulting in a similar score with a very little difference to each other. The Native and mutants P2683S and R2702C have similar interaction of -5.7 kcal/mol, -5.9 kcal/mol and − 5.6 kcal/mol respectively with Methyltestosterone followed by a binding score of -6 kcal/mol, -5.6 kcal/mol and − 5.8 kcal/mol respectively for Estradiol. Detailed study about the disease, effect of nsSNP’s and the response of the drug towards the mutation are the key factors in order to launch a new personalized medicine. Therefore, in this study using various computational prediction methods, molecular dynamics simulation and molecular docking studies we have determined the nsSNP’s responsible to cause CHARGE syndrome and the drug response with respect to the determined nsSNP mutations. The outcomes acquired from our investigation will provide the data for experimental biologists for the additional procedure for examining the rest of the variations in CDH7 protein.