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Potentially amyloidogenic conformational intermediates populate the unfolding landscape of transthyretin: Insights from molecular dynamics simulations

2010-02Journal article Restricted access
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datacite.subject.fosCiências Naturais::Ciências Biológicas
datacite.subject.sdg03:Saúde de Qualidade
datacite.subject.sdg07:Energias Renováveis e Acessíveis
datacite.subject.sdg11:Cidades e Comunidades Sustentáveis
dc.contributor.authorRodrigues, J. Rui
dc.contributor.authorSimões, Carlos J. V.
dc.contributor.authorSilva, Cândida G.
dc.contributor.authorBrito, Rui M. M.
dc.date.accessioned2025-12-15T18:11:16Z
dc.date.available2025-12-15T18:11:16Z
dc.date.issued2010-02
dc.description.abstractProtein aggregation into insoluble fibrillar structures known as amyloid characterizes several neurodegenerative diseases, including Alzheimer's, Huntington's and Creutzfeldt-Jakob. Transthyretin (TTR), a homotetrameric plasma protein, is known to be the causative agent of amyloid pathologies such as FAP (familial amyloid polyneuropathy), FAC (familial amyloid cardiomiopathy) and SSA (senile systemic amyloidosis). It is generally accepted that TTR tetramer dissociation and monomer partial unfolding precedes amyloid fibril formation. To explore the TTR unfolding landscape and to identify potential intermediate conformations with high tendency for amyloid formation, we have performed molecular dynamics unfolding simulations of WT-TTR and L55P-TTR, a highly amyloidogenic TTR variant. Our simulations in explicit water allow the identification of events that clearly discriminate the unfolding behavior of WT and L55P-TTR. Analysis of the simulation trajectories show that (i) the L55P monomers unfold earlier and to a larger extent than the WT; (ii) the single α-helix in the TTR monomer completely unfolds in most of the L55P simulations while remain folded in WT simulations; (iii) L55P forms, early in the simulations, aggregation-prone conformations characterized by full displacement of strands C and D from the main β-sandwich core of the monomer; (iv) L55P shows, late in the simulations, severe loss of the H-bond network and consequent destabilization of the CBEF β-sheet of the β-sandwich; (v) WT forms aggregation-compatible conformations only late in the simulations and upon extensive unfolding of the monomer. These results clearly show that, in comparison with WT, L55P-TTR does present a much higher probability of forming transient conformations compatible with aggregation and amyloid formation.eng
dc.description.sponsorshipFundação para a Ciência e a Tecnologia; Program FEDER, Portugal; Grant numbers: POCTI/BME/49583/2002, PTDC/BIA-PRO/72838/2006; Fellowship numbers: AI/06/02, SFRH/BD/16888/2004, SFRH/BD/29357/2006.
dc.description.sponsorshipThe authors thank the Center for Computational Physics, Departamento de Física, Universidade de Coimbra, Coimbra, Portugal, and the Computer Science and Technology Center, Departamento de Informática, Universidade do Minho, Braga, Portugal, for the computer resources provided.
dc.identifier.citationRodrigues, J.R., Simões, C.J.V., Silva, C.G. and Brito, R.M.M. (2010), Potentially amyloidogenic conformational intermediates populate the unfolding landscape of transthyretin: Insights from molecular dynamics simulations. Protein Science, 19: 202-219. https://doi.org/10.1002/pro.289.
dc.identifier.doi10.1002/pro.289
dc.identifier.eissn1469-896X
dc.identifier.issn0961-8368
dc.identifier.urihttp://hdl.handle.net/10400.8/15072
dc.language.isoeng
dc.peerreviewedyes
dc.publisherWiley
dc.relationSearching for high level rules in protein folding and unfolding: from amyloid diseases to protein structure prediction
dc.relationDATA MINING AND KNOWLEDGE EXTRACTION FROM PROTEIN UNFOLDING SIMULATIONS. A CONTRIBUTION FOR PROTEIN STRUCTURE PREDICTION
dc.relationTOWARDS NOVEL THERAPIES TO PREVENT AMYLOID DISEASES: COMBINING THE REACH OF VIRTUAL HIGH-THROUGHPUT SCREENING AND STRUCTURE-BASED RATIONAL LIGAND DESIGN
dc.relation.hasversionhttps://onlinelibrary.wiley.com/doi/10.1002/pro.289
dc.relation.ispartofProtein Science
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectamyloid
dc.subjectamyloidogenic intermediates
dc.subjectmolecular dynamics
dc.subjectprotein misfolding
dc.subjectprotein unfolding
dc.subjecttransthyretin
dc.subjectL55P-TTR
dc.titlePotentially amyloidogenic conformational intermediates populate the unfolding landscape of transthyretin: Insights from molecular dynamics simulationseng
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleSearching for high level rules in protein folding and unfolding: from amyloid diseases to protein structure prediction
oaire.awardTitleDATA MINING AND KNOWLEDGE EXTRACTION FROM PROTEIN UNFOLDING SIMULATIONS. A CONTRIBUTION FOR PROTEIN STRUCTURE PREDICTION
oaire.awardTitleTOWARDS NOVEL THERAPIES TO PREVENT AMYLOID DISEASES: COMBINING THE REACH OF VIRTUAL HIGH-THROUGHPUT SCREENING AND STRUCTURE-BASED RATIONAL LIGAND DESIGN
oaire.awardURIhttp://hdl.handle.net/10400.8/15069
oaire.awardURIhttp://hdl.handle.net/10400.8/15070
oaire.awardURIhttp://hdl.handle.net/10400.8/15071
oaire.citation.endPage219
oaire.citation.issue2
oaire.citation.startPage202
oaire.citation.titleProtein Science
oaire.citation.volume19
oaire.fundingStreamConcurso para Projectos de I&D em todos os Domínios Científicos - 2006
oaire.versionhttp://purl.org/coar/version/c_970fb48d4fbd8a85
person.familyNameRodrigues
person.givenNameJoaquim Rui
person.identifier.ciencia-id9018-0B83-E2C6
person.identifier.orcid0000-0002-9756-1124
person.identifier.ridL-4137-2014
person.identifier.scopus-author-id10242931100
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relation.isAuthorOfPublication.latestForDiscovery52f6ffb2-43e9-4f78-b414-dbac46f80305
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Protein aggregation into insoluble fibrillar structures known as amyloid characterizes several neurodegenerative diseases, including Alzheimer's, Huntington's and Creutzfeldt-Jakob. Transthyretin (TTR), a homotetrameric plasma protein, is known to be the causative agent of amyloid pathologies such as FAP (familial amyloid polyneuropathy), FAC (familial amyloid cardiomiopathy) and SSA (senile systemic amyloidosis). It is generally accepted that TTR tetramer dissociation and monomer partial unfolding precedes amyloid fibril formation. To explore the TTR unfolding landscape and to identify potential intermediate conformations with high tendency for amyloid formation, we have performed molecular dynamics unfolding simulations of WT-TTR and L55P-TTR, a highly amyloidogenic TTR variant. Our simulations in explicit water allow the identification of events that clearly discriminate the unfolding behavior of WT and L55P-TTR. Analysis of the simulation trajectories show that (i) the L55P monomers unfold earlier and to a larger extent than the WT; (ii) the single α-helix in the TTR monomer completely unfolds in most of the L55P simulations while remain folded in WT simulations; (iii) L55P forms, early in the simulations, aggregation-prone conformations characterized by full displacement of strands C and D from the main β-sandwich core of the monomer; (iv) L55P shows, late in the simulations, severe loss of the H-bond network and consequent destabilization of the CBEF β-sheet of the β-sandwich; (v) WT forms aggregation-compatible conformations only late in the simulations and upon extensive unfolding of the monomer. These results clearly show that, in comparison with WT, L55P-TTR does present a much higher probability of forming transient conformations compatible with aggregation and amyloid formation.
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