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Replica exchange molecular dynamics simulations reveal self-association sites in M-crystallin caused by mutations provide insights of cataract
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...
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8639718/ https://www.ncbi.nlm.nih.gov/pubmed/34857812 http://dx.doi.org/10.1038/s41598-021-02728-8 |
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author | Patel, Sunita Hosur, Ramakrishna V. |
author_facet | Patel, Sunita Hosur, Ramakrishna V. |
author_sort | Patel, Sunita |
collection | PubMed |
description | 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 Ca(2+) 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. |
format | Online Article Text |
id | pubmed-8639718 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-86397182021-12-06 Replica exchange molecular dynamics simulations reveal self-association sites in M-crystallin caused by mutations provide insights of cataract Patel, Sunita Hosur, Ramakrishna V. Sci Rep Article 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 Ca(2+) 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. Nature Publishing Group UK 2021-12-02 /pmc/articles/PMC8639718/ /pubmed/34857812 http://dx.doi.org/10.1038/s41598-021-02728-8 Text en © The Author(s) 2021, corrected publication 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Patel, Sunita Hosur, Ramakrishna V. Replica exchange molecular dynamics simulations reveal self-association sites in M-crystallin caused by mutations provide insights of cataract |
title | Replica exchange molecular dynamics simulations reveal self-association sites in M-crystallin caused by mutations provide insights of cataract |
title_full | Replica exchange molecular dynamics simulations reveal self-association sites in M-crystallin caused by mutations provide insights of cataract |
title_fullStr | Replica exchange molecular dynamics simulations reveal self-association sites in M-crystallin caused by mutations provide insights of cataract |
title_full_unstemmed | Replica exchange molecular dynamics simulations reveal self-association sites in M-crystallin caused by mutations provide insights of cataract |
title_short | Replica exchange molecular dynamics simulations reveal self-association sites in M-crystallin caused by mutations provide insights of cataract |
title_sort | replica exchange molecular dynamics simulations reveal self-association sites in m-crystallin caused by mutations provide insights of cataract |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8639718/ https://www.ncbi.nlm.nih.gov/pubmed/34857812 http://dx.doi.org/10.1038/s41598-021-02728-8 |
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