γD-Crystallin
(HγDC) is a key structural protein in
the human lens, whose aggregation has been associated with the development
of cataracts. Single-point mutations and post-translational modifications
destabilize HγDC interactions, forming partially folded intermediates,
where hydrophobic residues are exposed and thus triggering its aggregation.
In this work, we used alchemical free-energy calculations to predict
changes in thermodynamic stability (ΔΔG) of 10 alanine-scanning variants and 12 HγDC mutations associated
with the development of congenital cataract. Our results show that
W42R is the most destabilizing mutation in HγDC. This has been
corroborated through experimental determination of ΔΔG employing differential scanning calorimetry. Calculations
of hydration free energies from the HγDC WT and the W42R mutant
suggested that the mutant has a higher aggregation propensity. Our
combined theoretical and experimental results contribute to understand
HγDC destabilization and aggregation mechanisms in age-onset
cataracts.
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