Lanosterol reduces the aggregation propensity of ultraviolet-damaged human γD-crystallins: a molecular dynamics study

Ultraviolet (UV) radiation-induced oxidation of tryptophan (Trp) to kynurenine (KN) (TRP > KN) in human γD-crystallins (HγD-Crys) promotes the conversion of proteins into partially unfolded species that act as important precursors for sequential large-scale aggregation. Herein, we report that lan...

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Veröffentlicht in:Physical chemistry chemical physics : PCCP 2021-06, Vol.23 (24), p.13696-1374
Hauptverfasser: Zhou, Hong, Li, Youyun, Yang, Ying, Liu, Shengtang, Yang, Zaixing
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Li, Youyun
Yang, Ying
Liu, Shengtang
Yang, Zaixing
description Ultraviolet (UV) radiation-induced oxidation of tryptophan (Trp) to kynurenine (KN) (TRP > KN) in human γD-crystallins (HγD-Crys) promotes the conversion of proteins into partially unfolded species that act as important precursors for sequential large-scale aggregation. Herein, we report that lanosterol shows protective activity to the structure of the TRP > KN mutant HγD-Crys, particularly its N-terminal domain (N-td), by using all-atom molecular dynamics simulations. The Trp68 > KN mutation significantly destabilizes the originally highly stable "Tyr55-Trp68-Tyr62" cluster, thereby causing loop2, where the mutation occurs, to become very flexible. The large fluctuation of loop2 induces cracks, which appear on the protein surface, resulting in the intrusion of water molecules into the hydrophobic core of the N-td. This event eventually triggers the unfolding of the N-td. However, lanosterol can suppress the large fluctuation of loop2 to protect the structural stability of the mutant N-td, thus reducing the aggregation propensity of the TRP > KN mutant HγD-Crys. This structure protective activity of lanosterol arises from its capability to preferentially bind to the hydrophobic regions near loop2. Thus, lanosterol acts as a "water blocker" to prevent the invasion of solvent molecules into the hydrophobic core. These findings provide some valuable insights into the development of potential lanosterol-based drugs for cataract prevention and treatment. Lanosterol can stabilize the structure of ultraviolet-damaged human γD-crystallins ( e.g. , tryptophans were photo-oxidized to kynurenines), particularly its N-td, thus reducing its aggregation propensity.
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Herein, we report that lanosterol shows protective activity to the structure of the TRP &gt; KN mutant HγD-Crys, particularly its N-terminal domain (N-td), by using all-atom molecular dynamics simulations. The Trp68 &gt; KN mutation significantly destabilizes the originally highly stable "Tyr55-Trp68-Tyr62" cluster, thereby causing loop2, where the mutation occurs, to become very flexible. The large fluctuation of loop2 induces cracks, which appear on the protein surface, resulting in the intrusion of water molecules into the hydrophobic core of the N-td. This event eventually triggers the unfolding of the N-td. However, lanosterol can suppress the large fluctuation of loop2 to protect the structural stability of the mutant N-td, thus reducing the aggregation propensity of the TRP &gt; KN mutant HγD-Crys. This structure protective activity of lanosterol arises from its capability to preferentially bind to the hydrophobic regions near loop2. Thus, lanosterol acts as a "water blocker" to prevent the invasion of solvent molecules into the hydrophobic core. These findings provide some valuable insights into the development of potential lanosterol-based drugs for cataract prevention and treatment. Lanosterol can stabilize the structure of ultraviolet-damaged human γD-crystallins ( e.g. , tryptophans were photo-oxidized to kynurenines), particularly its N-td, thus reducing its aggregation propensity.</description><identifier>ISSN: 1463-9076</identifier><identifier>EISSN: 1463-9084</identifier><identifier>DOI: 10.1039/d1cp00132a</identifier><language>eng</language><publisher>Cambridge: Royal Society of Chemistry</publisher><subject>Agglomeration ; Crystal structure ; Crystallinity ; Hydrophobicity ; Molecular dynamics ; Mutation ; Oxidation ; Protective structures ; Proteins ; Radiation effects ; Structural stability ; Tryptophan ; Ultraviolet radiation ; Water chemistry</subject><ispartof>Physical chemistry chemical physics : PCCP, 2021-06, Vol.23 (24), p.13696-1374</ispartof><rights>Copyright Royal Society of Chemistry 2021</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c314t-aa497a17d332947b8e3c8e5612ba9bb30d26321287fdfeb66dd2a2c389ec998e3</citedby><cites>FETCH-LOGICAL-c314t-aa497a17d332947b8e3c8e5612ba9bb30d26321287fdfeb66dd2a2c389ec998e3</cites><orcidid>0000-0003-3521-6867</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27923,27924</link.rule.ids></links><search><creatorcontrib>Zhou, Hong</creatorcontrib><creatorcontrib>Li, Youyun</creatorcontrib><creatorcontrib>Yang, Ying</creatorcontrib><creatorcontrib>Liu, Shengtang</creatorcontrib><creatorcontrib>Yang, Zaixing</creatorcontrib><title>Lanosterol reduces the aggregation propensity of ultraviolet-damaged human γD-crystallins: a molecular dynamics study</title><title>Physical chemistry chemical physics : PCCP</title><description>Ultraviolet (UV) radiation-induced oxidation of tryptophan (Trp) to kynurenine (KN) (TRP &gt; KN) in human γD-crystallins (HγD-Crys) promotes the conversion of proteins into partially unfolded species that act as important precursors for sequential large-scale aggregation. Herein, we report that lanosterol shows protective activity to the structure of the TRP &gt; KN mutant HγD-Crys, particularly its N-terminal domain (N-td), by using all-atom molecular dynamics simulations. The Trp68 &gt; KN mutation significantly destabilizes the originally highly stable "Tyr55-Trp68-Tyr62" cluster, thereby causing loop2, where the mutation occurs, to become very flexible. The large fluctuation of loop2 induces cracks, which appear on the protein surface, resulting in the intrusion of water molecules into the hydrophobic core of the N-td. This event eventually triggers the unfolding of the N-td. However, lanosterol can suppress the large fluctuation of loop2 to protect the structural stability of the mutant N-td, thus reducing the aggregation propensity of the TRP &gt; KN mutant HγD-Crys. This structure protective activity of lanosterol arises from its capability to preferentially bind to the hydrophobic regions near loop2. Thus, lanosterol acts as a "water blocker" to prevent the invasion of solvent molecules into the hydrophobic core. These findings provide some valuable insights into the development of potential lanosterol-based drugs for cataract prevention and treatment. 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Herein, we report that lanosterol shows protective activity to the structure of the TRP &gt; KN mutant HγD-Crys, particularly its N-terminal domain (N-td), by using all-atom molecular dynamics simulations. The Trp68 &gt; KN mutation significantly destabilizes the originally highly stable "Tyr55-Trp68-Tyr62" cluster, thereby causing loop2, where the mutation occurs, to become very flexible. The large fluctuation of loop2 induces cracks, which appear on the protein surface, resulting in the intrusion of water molecules into the hydrophobic core of the N-td. This event eventually triggers the unfolding of the N-td. However, lanosterol can suppress the large fluctuation of loop2 to protect the structural stability of the mutant N-td, thus reducing the aggregation propensity of the TRP &gt; KN mutant HγD-Crys. This structure protective activity of lanosterol arises from its capability to preferentially bind to the hydrophobic regions near loop2. Thus, lanosterol acts as a "water blocker" to prevent the invasion of solvent molecules into the hydrophobic core. These findings provide some valuable insights into the development of potential lanosterol-based drugs for cataract prevention and treatment. Lanosterol can stabilize the structure of ultraviolet-damaged human γD-crystallins ( e.g. , tryptophans were photo-oxidized to kynurenines), particularly its N-td, thus reducing its aggregation propensity.</abstract><cop>Cambridge</cop><pub>Royal Society of Chemistry</pub><doi>10.1039/d1cp00132a</doi><tpages>9</tpages><orcidid>https://orcid.org/0000-0003-3521-6867</orcidid></addata></record>
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source Royal Society Of Chemistry Journals 2008-; Alma/SFX Local Collection
subjects Agglomeration
Crystal structure
Crystallinity
Hydrophobicity
Molecular dynamics
Mutation
Oxidation
Protective structures
Proteins
Radiation effects
Structural stability
Tryptophan
Ultraviolet radiation
Water chemistry
title Lanosterol reduces the aggregation propensity of ultraviolet-damaged human γD-crystallins: a molecular dynamics study
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