Human γD-crystallin (HγD-Crys) is a structural protein in the eye lens that plays a central role in maintaining lens transparency and refractive index. Its stability is governed by the proper folding of its two immunoglobulin-like domains. Aggregation of this protein disrupts solubility, leading to lens opacification and the development of cataracts. Cataracts will affect everyone if they live long enough. Once opacification occurs in the lens due to cataracts the only effective treatment is surgery. Preliminary results show that dithiolthreitol (DTT) is a promising inhibitor of the HγD-Crys aggregate. Computation chemistry tools are an ideal way to explore potential therapeutic strategies targeting protein aggregation because of the cost of time and resources being relatively low in comparison to other tools. In this work, there is no current HγD-Crys proteins in the protein database that already have the disulfide bond between chains that hold the aggregate together, because of this we apply high ambiguity driven protein-protein docking (HADDOCK 2.4) to dock the protein chains in close proximity to add the disulfide bond formation between Cys32 (Chain A) and Cys41 (Chain B). These cysteines need to be able to change protonation states because this aggregate will be simulated in an en vivo environment, constant pH molecular dynamics (CpHMD) simulations are employed to evaluate the effects of protonation states at physiological pH (∼7–8) on binding affinities and aggregation propensity. To further refine these predictions, quantum mechanics/molecular mechanics (QM/MM) hybrid simulations are used to investigate the disulfide bond that is holding the two chains together, this hybrid simulation is used to model the effect that potential inhibitors have on the disulfide bond specifically.
Kaiden Zaborowski (2026) studied this question.