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
N1 - Funding Information:
Cedrix J. Dongmo Foumthuim acknowledges the CINECA Projects HP10CCSKB9 and HP10CIWPJ4 for the availability of high performance computing resources and the Ph.D. fellowship provided by the “Ministero dell’Istruzione, dell’Universita e della Ricerca”.
Publisher Copyright:
© 2018 Cedrix J. Dongmo Foumthuim et al.
PY - 2018
Y1 - 2018
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.
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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 -