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Effects of a plant cyclotide on conformational dynamics and destabilization of β-amyloid fibrils through molecular dynamics simulations

Aggregation of β-amyloid (Aβ) peptide is one of the hallmarks of Alzheimer’s disease (AD) which results in chronic and progressive neurodegeneration of the brain. A recent study by our group have shown the ability of cyclic disulfide-rich peptides (“cyclotides”) isolated from a medicinal plant, Clit...

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Autores principales: Kalmankar, Neha V., Gehi, Bhuvaneshwari Rajendrakumar, Sowdhamini, Ramanathan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9561823/
https://www.ncbi.nlm.nih.gov/pubmed/36250019
http://dx.doi.org/10.3389/fmolb.2022.986704
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author Kalmankar, Neha V.
Gehi, Bhuvaneshwari Rajendrakumar
Sowdhamini, Ramanathan
author_facet Kalmankar, Neha V.
Gehi, Bhuvaneshwari Rajendrakumar
Sowdhamini, Ramanathan
author_sort Kalmankar, Neha V.
collection PubMed
description Aggregation of β-amyloid (Aβ) peptide is one of the hallmarks of Alzheimer’s disease (AD) which results in chronic and progressive neurodegeneration of the brain. A recent study by our group have shown the ability of cyclic disulfide-rich peptides (“cyclotides”) isolated from a medicinal plant, Clitoria ternatea, to inhibit the aggregation of Aβ peptides and reduce oxidative stress caused by reactive oxygen species using in vivo models of transgenic Caenorhabditis elegans. In the present study, through extensive computational docking and multi-ns molecular dynamics (MD) simulation, we evaluated if cyclotides can stably bind to Aβ molecules and/or destabilize the Aβ fibril by preventing conformational changes from α-helical to β-sheet rich structures. We demonstrate that cyclotides bind effectively and stably to different forms of Aβ structures via hydrogen bonding and hydrophobic interactions. One of the conserved hydrophobic interface residues, Tyr10 was mutated to Ala and the impact of this virtual mutation was estimated by additional MD simulations for the wild-type (WT) and mutant protein-peptide complexes. A detailed MD simulation analyses revealed that cyclotides form hydrogen bonds with the toxic amyloid assemblies thereby weakening the inter-strand hydrogen bonds between the Aβ peptide. The φ-ѱ distribution map of residues in the cyclotide binding pocket that ideally adopt β-sheet conformation show deviation towards right-handed ɑ-helical (ɑ(R)) conformation. This effect was similar to that observed for the Tyr10Ala mutant and doubly so, for the cyclotide bound form. It is therefore possible to hypothesise that the opening up of amyloid β-sheet is due to an unfolding process occurring in the Aβ caused by cyclotide binding and inhibition. Our current findings provide novel structural insights on the mode of interaction between cyclotides and Aβ fibrils and describe their anti-amyloid aggregation potential. This sheds light on the future of cyclotide-based drug design against protein aggregation, a hallmark event in many neurodegenerative diseases.
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spelling pubmed-95618232022-10-15 Effects of a plant cyclotide on conformational dynamics and destabilization of β-amyloid fibrils through molecular dynamics simulations Kalmankar, Neha V. Gehi, Bhuvaneshwari Rajendrakumar Sowdhamini, Ramanathan Front Mol Biosci Molecular Biosciences Aggregation of β-amyloid (Aβ) peptide is one of the hallmarks of Alzheimer’s disease (AD) which results in chronic and progressive neurodegeneration of the brain. A recent study by our group have shown the ability of cyclic disulfide-rich peptides (“cyclotides”) isolated from a medicinal plant, Clitoria ternatea, to inhibit the aggregation of Aβ peptides and reduce oxidative stress caused by reactive oxygen species using in vivo models of transgenic Caenorhabditis elegans. In the present study, through extensive computational docking and multi-ns molecular dynamics (MD) simulation, we evaluated if cyclotides can stably bind to Aβ molecules and/or destabilize the Aβ fibril by preventing conformational changes from α-helical to β-sheet rich structures. We demonstrate that cyclotides bind effectively and stably to different forms of Aβ structures via hydrogen bonding and hydrophobic interactions. One of the conserved hydrophobic interface residues, Tyr10 was mutated to Ala and the impact of this virtual mutation was estimated by additional MD simulations for the wild-type (WT) and mutant protein-peptide complexes. A detailed MD simulation analyses revealed that cyclotides form hydrogen bonds with the toxic amyloid assemblies thereby weakening the inter-strand hydrogen bonds between the Aβ peptide. The φ-ѱ distribution map of residues in the cyclotide binding pocket that ideally adopt β-sheet conformation show deviation towards right-handed ɑ-helical (ɑ(R)) conformation. This effect was similar to that observed for the Tyr10Ala mutant and doubly so, for the cyclotide bound form. It is therefore possible to hypothesise that the opening up of amyloid β-sheet is due to an unfolding process occurring in the Aβ caused by cyclotide binding and inhibition. Our current findings provide novel structural insights on the mode of interaction between cyclotides and Aβ fibrils and describe their anti-amyloid aggregation potential. This sheds light on the future of cyclotide-based drug design against protein aggregation, a hallmark event in many neurodegenerative diseases. Frontiers Media S.A. 2022-09-30 /pmc/articles/PMC9561823/ /pubmed/36250019 http://dx.doi.org/10.3389/fmolb.2022.986704 Text en Copyright © 2022 Kalmankar, Gehi and Sowdhamini. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Molecular Biosciences
Kalmankar, Neha V.
Gehi, Bhuvaneshwari Rajendrakumar
Sowdhamini, Ramanathan
Effects of a plant cyclotide on conformational dynamics and destabilization of β-amyloid fibrils through molecular dynamics simulations
title Effects of a plant cyclotide on conformational dynamics and destabilization of β-amyloid fibrils through molecular dynamics simulations
title_full Effects of a plant cyclotide on conformational dynamics and destabilization of β-amyloid fibrils through molecular dynamics simulations
title_fullStr Effects of a plant cyclotide on conformational dynamics and destabilization of β-amyloid fibrils through molecular dynamics simulations
title_full_unstemmed Effects of a plant cyclotide on conformational dynamics and destabilization of β-amyloid fibrils through molecular dynamics simulations
title_short Effects of a plant cyclotide on conformational dynamics and destabilization of β-amyloid fibrils through molecular dynamics simulations
title_sort effects of a plant cyclotide on conformational dynamics and destabilization of β-amyloid fibrils through molecular dynamics simulations
topic Molecular Biosciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9561823/
https://www.ncbi.nlm.nih.gov/pubmed/36250019
http://dx.doi.org/10.3389/fmolb.2022.986704
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