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:	Sunita Patel, Ramakrishna V. Hosur
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/63b613eb87fe43fcae40f76f8647a4c6
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spelling	oai:doaj.org-article:63b613eb87fe43fcae40f76f8647a4c62021-12-05T12:14:28ZReplica exchange molecular dynamics simulations reveal self-association sites in M-crystallin caused by mutations provide insights of cataract10.1038/s41598-021-02728-82045-2322https://doaj.org/article/63b613eb87fe43fcae40f76f8647a4c62021-12-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-02728-8https://doaj.org/toc/2045-2322Abstract 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.Sunita PatelRamakrishna V. HosurNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Sunita Patel Ramakrishna V. Hosur Replica exchange molecular dynamics simulations reveal self-association sites in M-crystallin caused by mutations provide insights of cataract
description	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.
format	article
author	Sunita Patel Ramakrishna V. Hosur
author_facet	Sunita Patel Ramakrishna V. Hosur
author_sort	Sunita Patel
title	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_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_sort	replica exchange molecular dynamics simulations reveal self-association sites in m-crystallin caused by mutations provide insights of cataract
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/63b613eb87fe43fcae40f76f8647a4c6
work_keys_str_mv	AT sunitapatel replicaexchangemoleculardynamicssimulationsrevealselfassociationsitesinmcrystallincausedbymutationsprovideinsightsofcataract AT ramakrishnavhosur replicaexchangemoleculardynamicssimulationsrevealselfassociationsitesinmcrystallincausedbymutationsprovideinsightsofcataract
_version_	1718372136720007168

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

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