Replica exchange molecular dynamics simulations reveal self-association sites in M-crystallin caused by mutations provide insights of cataract
Abstract Crystallins are ubiquitous, however, prevalence is seen in eye lens. Eye lens crystallins are long-lived and structural intactness is required for maintaining lens transparency and protein solubility. Mutations in crystallins often lead to cataract. In this study, we performed mutations at...
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| Autores principales: | , |
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| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
Nature Portfolio
2021
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| Materias: | |
| Acceso en línea: | https://doaj.org/article/63b613eb87fe43fcae40f76f8647a4c6 |
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| Sumario: | Abstract Crystallins are ubiquitous, however, prevalence is seen in eye lens. Eye lens crystallins are long-lived and structural intactness is required for maintaining lens transparency and protein solubility. Mutations in crystallins often lead to cataract. In this study, we performed mutations at specific sites of M-crystallin, a close homologue of eye lens crystallin and studied by using replica exchange molecular dynamics simulation with generalized Born implicit solvent model. Mutations were made on the Ca2+ binding residues (K34D and S77D) and in the hydrophobic core (W45R) which is known to cause congenital cataract in homologous γD-crystallin. The chosen mutations caused large motion of the N-terminal Greek key, concomitantly broke the interlocking Greek keys interactions and perturbed the compact core resulting in several folded and partially unfolded states. Partially unfolded states exposed large hydrophobic patches that could act as precursors for self-aggregation. Accumulation of such aggregates is the potential cause of cataract in homologous eye lens crystallins. |
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