Computational analysis of histidine mutations on the structure stability of human tyrosinases leading to albinism insurgence

Misfolding and structural alteration in proteins lead to serious malfunctions and cause various diseases in human. Mutations at the active binding site in tyrosinase impair structural stability and cause lethal albinism by abolishing the copper-binding. To evaluate the histidine mutational effect all the mutated structures were built using homology modelling. The protein sequence was retrieved from UniProt database and 3D models of original and mutated human tyrosinases sequences were predicted by changing the residual positions within the target sequence separately. Structural and mutational analyses were performed to interpret the significance of mutated residues (N180, R202, Q202, R211, Y363, R367, Y367 and D390) at the active binding site of tyrosinases. Cspritz analysis depicted that 23.25% residues actively participate in the unstability of tyrosinase. The accuracy of predicted models was confirmed through online servers ProSA-Web ERRAT Score and VERIFY 3D values. The theoretical pI and GRAVY generated results also showed the accuracy of predicted models. The CCA negative correlation results depicted that the replacement of mutated residues at His within active binding site disturb the structural stability of tyrosianses. The predicted CCA scores of Tyr367 (-0.079) and Q/R202 (0.032) exposed that both mutations have more potential to disturb the structural stability. MD simulation analyses of all predicted models justified that Gln202, Arg202, Tyr367 and D390 replacement made the protein structures more susceptible to destabilization. Mutational results showed that the replacement of His with Q/R 202 and Y/R363 have lethal effect and may cause melanin associated disease such as OCA1. Taken together, our computational analysis depicts that the mutated residues such as Q/R202 and Y/R363 actively participate in unstability and misfolding of tyrosinase which may govern OCA1 through disturbing the melanin biosynthetic pathway.