Effects of Mutating Trp42 Residue on γD-Crystallin Stability

Abstract

Oligomerization and aggregation of γD-crystallins (HγDC) in the eye lens is one of the main causes of cataract development. To date, several congenital mutations related to this protein are known to promote the formation of aggregates. Previous studies have demonstrated that mutations in W42 residue of HγDC lead to the generation of partially unfolded intermediates that are more prone to aggregate. To understand the role of W42 in the stability of HγDC, we performed alchemical free-energy calculations and all-atom molecular dynamics simulations of different W42 mutant models. Our results suggest that substitution of W42 by small size and/or polar residues promotes HγDC denaturation due to the entry of water molecules into the hydrophobic core of the N-terminal domain. Similar behavior was observed in the C-terminal domain of HγDC when mutating the W130 residue located in a homologous position. Moreover, the exposure of the hydrophobic core residues could lead to the formation of aggregation-prone partially unfolded species. Overall, this study takes a step toward understanding the role of HγDC in cataract development.

Replica exchange molecular dynamics simulations reveal self-association sites in M-crystallin caused by mutations provide insights of cataract

“…This mutant shows a large hydrophobic exposure and can acts as primary sites for aggregation 65 . In another simulation study, W42 is mutated to polar residues such as Lys and Arg which denatures the Greek key domain as solvent enter into the core and causes hydrophobic exposure of the core residues 66 . In all these studies W42 mutation leading to perturbation of hydrophobic core is accompanied by hydrophobic exposure which is a common event irrespective of different independent studies.…”

“…There is an intricate relation between unfolding and aggregation 5 , 67 , 68 . V75D, W42R mutations in γD-crystallin 28 , 65 , 66 , 69 , G75V mutation in γS-crystallin 69 , S228P in βB1-crystallin 70 are associated with partial unfolding leading to hydrophobic exposure. Our study affirm that partially unfolded species are formed due to mutations which can serve as precursors for aggregation and can lead to cataract.…”

Replica Exchange Molecular Dynamics Simulations Reveal Self-association Sites in M- Crystallin Caused by Mutations Provide Insights of Cataract

“…In another multiscale atomistic simulation of γD-crystallin having W42R mutation, adopted a distinct conformation in solution where Greek key domains are more of less intact while a large perturbation is observed in the inter-domain interface region which shows large hydrophobic exposure and can act as primary sites for aggregation 52 . In another simulation study, W42 is mutated to polar residues such as Lys and Arg which denatures the Greek key domain as solvent enter into the core and causes hydrophobic exposure of core residues 53 . In all these studies W42 mutation leading to perturbation in the hydrophobic core accompanied by hydrophobic exposure is the common event irrespective of different independent studies.…”

“…There is an intricate relation between unfolding and aggregation 4,54,55 . V75D, W42R mutations in γD-crystallin [51][52][53]56 , G75V mutation in γS-crystallin 56 , S228P in βB1-crystallin 57 associated with partial unfolding leading to hydrophobic exposure. Our study a rm that partially unfolded species are formed due to mutation which could serve as precursors for aggregation and can develop cataract.…”

Outlook on the Development and Application of Molecular Simulations in Latin America

“…MD simulations proved to be one of the most popular computational chemistry tools. In this special issue, atomistic MD simulations have been applied in many studies to understand key structural and functional properties of proteins, − receptor activation, insights into the binding of ligands, − mutations, ,− protein folding, and inhibitor design . In addition, combined free energy simulations and NMR chemical-shift perturbation has been utilized to identify transient cation-π contacts in proteins .…”