Dynamics and Thermodynamics of Transthyretin Association from Molecular Dynamics Simulations.

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

doi:10.1155/2018/7480749

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.

Highlights

IntroductionTransthyretin (TTR) is a 55 kDa globular oligomeric protein made up by four identical monomeric units (I-IV, see Figure 1(a)) each composed of 127 amino acid residues
Molecular dynamics simulations were 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/S117 by E (S117E) (3M-TTR), in relation to wild-type
The analysis of trajectories reveals that mutations do not have major impact on protein structure, and the thermodynamic analysis confirms this picture

Summary

Introduction

Transthyretin (TTR) is a 55 kDa globular oligomeric protein made up by four identical monomeric units (I-IV, see Figure 1(a)) each composed of 127 amino acid residues. Before being released into plasma, TTR is principally produced in liver, choroids plexus, and retina [1,2,3,4]. The 3D-conformation of all TTR-tetramers displays high degree of symmetry as shown at high resolution by Blake and coworkers [8] and Hornberg et al [9]. TTR is an overall β-sheet protein with a small αhelix domain between strands E and F (see Figure 1(a))

Objectives

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Conclusion