Computational analysis of variant in tyrosinase protein using molecular dynamic simulation: An in silico approach

Schematic flowchart showing design of this study. Vitiligo is the most common skin depigmentation disorder, characterized by skin or mucous membrane depigmentation. It has a prevalence rate of 0.5 % to 2.0 %. It has an effect on the patient’s appearance and is known to cause mental problems such as anxiety and depression. Vitiligo appears to be a multigenic condition based on the pattern of inheritance, which skips generations but obviously clusters within families. The TYR (Tyrosinase) as categorized as a protein coding gene diseases associated linked with encompass albinism, oculocutaneous, typeIA, Albinism, Oculocutaneous and Type IB. TYR gene is located on human chromosome 11q14.3. This gene is about 117844 bp long starting from the molecular location 89177875 to 89295759 base pairs on chromosome 11 according to Homo Sapiens Annotation Release 110, GRCh38.p14 (NCBI), which includes 6 exons. In this current study an effort was put into the identification of SNP which change the structure and function of coded protein TYR . We have checked the pathogenicity of mutation (c.575C > A resulting into p.Ser192 TYR ) with the help of different computational protein prediction tools e.g. POLYPHEN-2, phd-SNP, Panther, SNP&GO, PredictSNP, I-Mutant and Mupro identified the SNP as disease causing. We conclude that mutation p.Ser192 TYR changing the structural confirmation of protein due which effect on the stability of protein resulting into disease. The stability analysis of the tyrosinase protein was conducted using the I-Mutant and Mupro server. Gene-gene interactions were explored through STRING. Energy minimization was performed on both wild and mutant protein revealing substantial differences. The biovia discovery studio was utilized to superimpose the model structure of wild and mutant protein, illustrating difference in protein helix fold. The study offer in silico evidence of vitiligo as a protein folding disorder. Molecular docking analysis revealed that the tyrosinase protein significantly altered stability in the active binding site and surrounding ligand interaction surface. Then a, 100 ns MD simulation was conducted to validate the behavior of the complex structure formed the vitiligo protein under in silico physiological condition and explore its temporal stability. The results demonstrated consistent conformation and binding pattern within simulated environment enriched drug derivatives. Furthermore, to check the identification of structural and functional annotated the TYR gene as both biological process and molecular function.