Gaucher’s Disease (GD) is a rare recessive disorder produced by the dysfunction of the lysosomal enzyme Glucocerebrosidase (GCase). GCase catalyses the cleavage of the glycolipid Glucosylceramide. The lack of functional GCase leads to the accumulation of its lipid substrate in lysosomes causing GD. GD presents a great phenotypic variation, symptoms ranging from asymptomatic adults to early childhood death due to neurological damage. More than 250 mutations in the protein GCase have been discovered that result in GD. Being able to link structural modifications of each mutation to the phenotypic variation of GD would enhance the understanding of the disease. The aim of this work is to understand the structural dynamics of wild type and mutant GCase. A model of the complex of the enzyme GCase with its facilitator protein, Saposin-C (Sap-C) was generated using Protein-Protein docking (PPD). In this work, a knowledge-based docking protocol that considers experimental data of protein- protein binding has been carried out. Here, a reliable model of the enzyme GCase with its facilitator protein is presented and is consistent with the experimental data. To understand the structural mechanism of function of the enzyme GCase, it was imperative to study its structural dynamics and conformational changes influenced by its interaction with other components including lipid bilayer, facilitator protein or substrate. Coarse-Grained MD (CG-MD) was employed to study lipid self-assembly and membrane insertion of the complex. Classical Atomistic MD (AT-MD) was used to study the dynamics of the interactions between different components of the simulation. Furthermore, the results of ten different AT-MD simulations sampling 9 s have been analysed. An activation method of GCase by Sap-C has been proposed, the change in conformation of GCase when its facilitator protein is present has been highlighted, through the stabilization of the loops at the entrance of the binding site. The differences in protein-protein binding when GCase is mutated have also been emphasised. Finally, Anharmonic Conformational Analysis and Markov State Models have been used to build a kinetic model of the system. This model supports our activation mechanism hyphothesis
