Journal
BIOMED RESEARCH INTERNATIONAL
Volume 2018, Issue -, Pages -Publisher
HINDAWI LTD
DOI: 10.1155/2018/7480749
Keywords
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Funding
- CINECA Projects [HP10CCSKB9, HP10CIWPJ4]
- Ministero dell'Istruzione, dell'Universita e della Ricerca
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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 beta-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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