Abstract
Oculocutaneous albinism type 1 is a genetic disorder caused by the disruption of tyrosinase activity in the melanogenesis pathway. The tyrosinase's intramelanosomal domain can be subdivided into the catalytic and Cys-rich subdomains, integral for protein stability and catalytic activity. To understand the motions in the tyrosinase intra-melanosomal subdomains and their link to its catalytic activity, we perform essential dynamics on homology models for tyrosinase and the mutant variants R217Q, R402Q, and R217Q/R402Q. Dimensional reduction techniques, such as Principal Component Analysis (PCA), are fundamental to systematically comprehending collective motions in protein structure. The alpha-carbon atomic coordinates for all residues across a 100 ns molecular dynamic trajectory were input into the PCA function, and the results were analyzed alongside correlated movements and free energy profiles for each protein structure. The PCA-identified coordinated movement underlying the stable conformations of wild-type tyrosinase arises within the H9 and H10 helices, which are proximal to the flexible tunnel system and the interface of the catalytic and Cys-rich subdomains. In contrast, genetic mutations R217Q and R217Q/R402Q disrupt the coordinated movement of the tyrosinase intra-melanosomal domain, indicating a cause of mutant variant instability.