| Autor: |
Kacirani A; Department of Chemical and Environmental Engineering, Yale University, New Haven, Connecticut 06520, United States.; Integrated Graduate Program in Physical and Engineering Biology, Yale University, New Haven, Connecticut 06520, United States., Uralcan B; Department of Chemical and Environmental Engineering, Yale University, New Haven, Connecticut 06520, United States.; Department of Chemical Engineering, Boğaziçi University, Istanbul 34342, Turkey., Domingues TS; Department of Chemical and Environmental Engineering, Yale University, New Haven, Connecticut 06520, United States.; Graduate Program in Applied Mathematics, Yale University, New Haven, Connecticut 06520, United States., Haji-Akbari A; Department of Chemical and Environmental Engineering, Yale University, New Haven, Connecticut 06520, United States. |
| Abstrakt: |
Human γD-crystallin belongs to a crucial family of proteins known as crystallins located in the fiber cells of the human lens. Since crystallins do not undergo any turnover after birth, they need to possess remarkable thermodynamic stability. However, their sporadic misfolding and aggregation, triggered by environmental perturbations or genetic mutations, constitute the molecular basis of cataracts, which is the primary cause of blindness in the globe according to the World Health Organization. Here, we investigate the impact of high pressure on the conformational landscape of wild-type HγD-crystallin using replica exchange molecular dynamics simulations augmented with principal component analysis. We find pressure to have a modest impact on global measures of protein stability, such as root-mean-square displacement and radius of gyration. Upon projecting our trajectories along the first two principal components from principal component analysis, however, we observe the emergence of distinct free energy basins at high pressures. By screening local order parameters previously shown or hypothesized as markers of HγD-crystallin stability, we establish correlations between a tyrosine-tyrosine aromatic contact within the N-terminal domain and the protein's end-to-end distance with projections along the first and second principal components, respectively. Furthermore, we observe the simultaneous contraction of the hydrophobic core and its intrusion by water molecules. This exploration sheds light on the intricate responses of HγD-crystallin to elevated pressures, offering insights into potential mechanisms underlying its stability and susceptibility to environmental perturbations, crucial for understanding cataract formation. |
