Conformational stability of the deamidated and mutated human βB2-crystallin

Abstract

Previous studies propose that genetic mutations and post-translational modifications in protein crystallins promote protein aggregation and are considered significant risk factors for cataract formation. The βB2-crystallin (HβB2C) forms a high proportion of proteins in the human eye lens. Different congenital mutations and post-translational deamidations in βB2-crystallin have been reported and linked to cataract formation. In this work, we employed extensive all-atom molecular dynamics simulations to evaluate the conformational stability of deamidated and mutated HβB2C. Our results show critical changes in the protein surface and its native contacts due to a modification in the conformational equilibrium of these proteins. The double deamidated (Q70E/Q162E) and single deamidated (Q70E) impact the well compact conformation of the HβB2C. These post-translational modifications allow the exposure of the protein hydrophobic interface, which lead to the exposure of electronegative residues. On the other hand, our mutational studies showed that the S143F mutation modifies the hydrogen-bond network of an antiparallel β-sheet, unfolding the C-terminal domain. Interestingly, the chain termination mutation (Q155X) does not unfold the N-terminal domain. However, the resultant conformation is more compact and avoids the exposure of the hydrophobic interface. Our results provide valuable information about the first steps of HβB2C unfolding in the presence of deamidated amino acids that have been reported to appear during aging. The findings reported in this work are essential for the general knowledge of the initial steps in the cataract formation mechanism, which may be helpful for the further development of molecules with pharmacological potential against cataract disease.