The human gammaD-crystallin (HγD-Crys) is a protein in the human eye that plays a critical role in maintaining lens transparency. The structure consists of two immunoglobulin-like domains, in which the folding determines the stability and solubility of the lens. The converse is true, such that aggregation or misfolding can lead to lens opacification. The gene mutation of the lens lowers its solubility, causing aggregates that lead to cataracts. Current treatments for cataracts entail laser-assisted cataract surgery, etc. However, the treatments are not addressing protein aggregation. The purpose of this project is to find a potential treatment to disaggregate HγD-Crys through a novel drug design. Since there are no known experimental structures of the HγD-Crys aggregate, HADDOCK is being utilized to generate potential structures of two HγD-Crys proteins in close proximity, creating a linking covalent disulfide bond. Other computational methods such as constant pH molecular dynamics (CpHMD) will be used to study the nature of protonation states at ∼ 7–8 pH, to help determine the function of cysteine residues in HγD-Crys. From this, the stabilization of aggregates is hoped to be achieved due to the favorable electrostatic interactions. The HγD-Crystallin protein has many cysteine residues that can take part in forming a disulfide bond. To achieve the most stable protein structure, Cys 32 (Chain A) and Cys 41 (Chain B) are known to be important in promoting aggregation. This bond has been noted to contribute to cataract formation via aggregation since it locks aggregation-prone intermediates. Ligands will undergo quantum mechanics/molecular mechanics (QM/MM) simulations using AMBER to analyze the ligand-protein chemical interactions. Ultimately, the determination of a promising ligand could lead to novel therapies for cataract treatments.
Suhani Patel (Sun,) studied this question.