Understanding the Unfolding Mechanisms of ??D Crystallin using Molecular Dynamics Simulations

γD-Crystallins being the longest-lived proteins are responsible for maintaining the transparency and refractivity of the lens. The unfolding of γD-Crys results in large insoluble aggregates which leads to cataracts. However, the unfolding pathway of γD-Crys is still unclear due to experimental constraints. One of the approaches to address this is through understanding the pathways of aggregation as well as determining the major forces driving the formation of these aggregates using Molecular Dynamic Simulations. Our initial results show that isolated greek key motifs of γD-Crys tend to unfold while the domains are found to be stable. This indicates that the domains are stabilized by strong hydrophobic intermotif interactions, whereas the motifs are destabilized when exposed to solvent by disrupting the hydrophobic core. Further, our mutation studies show that by replacing the hydrophobic residues Ile3 and Trp42 with charged residues the domain unfolds, which infers that Ile3 and Trp42 play a major role in stabilizing the protein. Our findings can help to predict potential drug targets, which will help γD-crystallin to retain its native conformation and provide an economically viable solution to treat cataracts.

Keywords: Cataract, Molecular Dynamics Simulations, Crystallin