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BioMed Research International
Volume 2018, Article ID 7480749, 14 pages
https://doi.org/10.1155/2018/7480749
Research Article

Dynamics and Thermodynamics of Transthyretin Association from Molecular Dynamics Simulations

1Dipartimento di Area Medica, Università di Udine, Piazzale Kolbe 4, 33100 Udine, Italy
2Istituto Nazionale Biostrutture e Biosistemi, Viale Medaglie d'Oro 305, 00136 Roma, Italy
3Department of Chemical Sciences, Life Sciences and Environmental Sustainability, University of Parma, Parco Area delle Scienze 23/A, 43124 Parma, Italy
4Dipartimento di Scienze Matematiche, Informatiche e Fisiche, Università di Udine, Via delle Scienze 206, 33100 Udine, Italy
5Science and Math Division, New York University at Abu Dhabi, P.O. Box 129188, Abu Dhabi, UAE

Correspondence should be addressed to Cedrix J. Dongmo Foumthuim; moc.liamg@58xirdec

Received 16 February 2018; Accepted 6 May 2018; Published 5 June 2018

Academic Editor: Carmen Domene

Copyright © 2018 Cedrix J. Dongmo Foumthuim et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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 -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.