Dynamics and Thermodynamics of Transthyretin Association from Molecular Dynamics Simulations

Cedrix J. Dongmo Foumthuim, Alessandra Corazza, Rodolfo Berni, Gennaro Esposito, Federico Fogolari

Research output: Contribution to journalArticle

Abstract

Molecular dynamics simulations are used in this work to probe the structural stability and the dynamics of engineered mutants of transthyretin (TTR), i.e., the double mutant F87M/L110M (MT-TTR) and the triple mutant F87M/L110M/S117E (3M-TTR), in relation to wild-type. Free energy analysis from end-point simulations and statistical effective energy functions are used to analyze trajectories, revealing that mutations do not have major impact on protein structure but rather on protein association, shifting the equilibria towards dissociated species. The result is confirmed by the analysis of 3M-TTR which shows dissociation within the first 10 ns of the simulation, indicating that contacts are lost at the dimer-dimer interface, whereas dimers (formed by monomers which pair to form two extended β-sheets) appear fairly stable. Overall the simulations provide a detailed view of the dynamics and thermodynamics of wild-type and mutant transthyretins and a rationale of the observed effects.

Original languageEnglish (US)
Article number7480749
JournalBioMed Research International
Volume2018
DOIs
StatePublished - Jan 1 2018

Fingerprint

Prealbumin
Molecular Dynamics Simulation
Thermodynamics
Molecular dynamics
Dimers
Computer simulation
Free energy
Proteins
Monomers
Trajectories
Association reactions
Mutation

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

Dynamics and Thermodynamics of Transthyretin Association from Molecular Dynamics Simulations. / Dongmo Foumthuim, Cedrix J.; Corazza, Alessandra; Berni, Rodolfo; Esposito, Gennaro; Fogolari, Federico.

In: BioMed Research International, Vol. 2018, 7480749, 01.01.2018.

Research output: Contribution to journalArticle

Dongmo Foumthuim, Cedrix J. ; Corazza, Alessandra ; Berni, Rodolfo ; Esposito, Gennaro ; Fogolari, Federico. / Dynamics and Thermodynamics of Transthyretin Association from Molecular Dynamics Simulations. In: BioMed Research International. 2018 ; Vol. 2018.
@article{898a9b263b234603817b1aa016cb9b80,
title = "Dynamics and Thermodynamics of Transthyretin Association from Molecular Dynamics Simulations",
abstract = "Molecular dynamics simulations are used in this work to probe the structural stability and the dynamics of engineered mutants of transthyretin (TTR), i.e., the double mutant F87M/L110M (MT-TTR) and the triple mutant F87M/L110M/S117E (3M-TTR), in relation to wild-type. Free energy analysis from end-point simulations and statistical effective energy functions are used to analyze trajectories, revealing that mutations do not have major impact on protein structure but rather on protein association, shifting the equilibria towards dissociated species. The result is confirmed by the analysis of 3M-TTR which shows dissociation within the first 10 ns of the simulation, indicating that contacts are lost at the dimer-dimer interface, whereas dimers (formed by monomers which pair to form two extended β-sheets) appear fairly stable. Overall the simulations provide a detailed view of the dynamics and thermodynamics of wild-type and mutant transthyretins and a rationale of the observed effects.",
author = "{Dongmo Foumthuim}, {Cedrix J.} and Alessandra Corazza and Rodolfo Berni and Gennaro Esposito and Federico Fogolari",
year = "2018",
month = "1",
day = "1",
doi = "10.1155/2018/7480749",
language = "English (US)",
volume = "2018",
journal = "BioMed Research International",
issn = "2314-6133",
publisher = "Hindawi Publishing Corporation",

}

TY - JOUR

T1 - Dynamics and Thermodynamics of Transthyretin Association from Molecular Dynamics Simulations

AU - Dongmo Foumthuim, Cedrix J.

AU - Corazza, Alessandra

AU - Berni, Rodolfo

AU - Esposito, Gennaro

AU - Fogolari, Federico

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Molecular dynamics simulations are used in this work to probe the structural stability and the dynamics of engineered mutants of transthyretin (TTR), i.e., the double mutant F87M/L110M (MT-TTR) and the triple mutant F87M/L110M/S117E (3M-TTR), in relation to wild-type. Free energy analysis from end-point simulations and statistical effective energy functions are used to analyze trajectories, revealing that mutations do not have major impact on protein structure but rather on protein association, shifting the equilibria towards dissociated species. The result is confirmed by the analysis of 3M-TTR which shows dissociation within the first 10 ns of the simulation, indicating that contacts are lost at the dimer-dimer interface, whereas dimers (formed by monomers which pair to form two extended β-sheets) appear fairly stable. Overall the simulations provide a detailed view of the dynamics and thermodynamics of wild-type and mutant transthyretins and a rationale of the observed effects.

AB - Molecular dynamics simulations are used in this work to probe the structural stability and the dynamics of engineered mutants of transthyretin (TTR), i.e., the double mutant F87M/L110M (MT-TTR) and the triple mutant F87M/L110M/S117E (3M-TTR), in relation to wild-type. Free energy analysis from end-point simulations and statistical effective energy functions are used to analyze trajectories, revealing that mutations do not have major impact on protein structure but rather on protein association, shifting the equilibria towards dissociated species. The result is confirmed by the analysis of 3M-TTR which shows dissociation within the first 10 ns of the simulation, indicating that contacts are lost at the dimer-dimer interface, whereas dimers (formed by monomers which pair to form two extended β-sheets) appear fairly stable. Overall the simulations provide a detailed view of the dynamics and thermodynamics of wild-type and mutant transthyretins and a rationale of the observed effects.

UR - http://www.scopus.com/inward/record.url?scp=85049115440&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85049115440&partnerID=8YFLogxK

U2 - 10.1155/2018/7480749

DO - 10.1155/2018/7480749

M3 - Article

C2 - 29967786

AN - SCOPUS:85049115440

VL - 2018

JO - BioMed Research International

JF - BioMed Research International

SN - 2314-6133

M1 - 7480749

ER -