Analysis of amyloidogenic transthyretin mutations using continuum solvent free energy calculations

Abstract

Many proteins can undergo pathological conformational changes that result in the formation of amyloidogenic fibril structures. Various neurodegenerative diseases are associated with such pathological fibril formation of specific proteins. Transthyretin (TTR) is a tetrameric globular transport protein in the blood plasma that can dissociate, unfold, and form long and stable fibrils. Many TTR mutations are known that promote (TTR) amyloidosis and cause severe diseases. TTR amyloidosis has been studied extensively using biochemical methods and structures of various mutations in the globular form have been characterized. Recently, also the structure of a TTR fibril has been determined. In an effort to better understand why some mutations increase or decrease the tendency of amyloid formation, we have applied a combined molecular dynamics and continuum solvent approach to calculate the energetic influence of residue changes in the globular versus fibril form. For 29 out of 36 tested TTR single residue mutations, the approach correctly predicts the increased or decreased tendency for amyloidosis allowing us also to elucidate the origins of the tendency. We find that indeed the destabilization of the globular monomer or changes in dimer and tetramer stability due to mutation has a dominant influence on the amyloidogenic tendency. The continuum solvent model predicts a significantly more favorable mean energy per residue of the fibril form compared to the globular form. This effect is only slightly modulated by single‐point mutations preserving the energetic preference for fibril formation upon protein unfolding. It explains why no correlation between experimental amyloidosis and calculated change in fibril stability was observed.

Atomic Mechanisms of Transthyretin Tetramer Dissociation Studied by Molecular Dynamics Simulations

“…67,68 Meanwhile, a recent work suggested that mutations at A108 and T119 with large residues, e.g., A108W, A108 V, T119M, and T119W, increased the tetramer's stability by filling the empty cavity at the interface. 69 Therefore, we can confirm that water plays a role in driving the tetramer dissociation of TTR.…”

“…Silva et al reported that water can disrupt hydrophobic interactions and eliminate water-excluded cavities . By using high hydrostatic pressure, Ferrão-Gonzales et al found that TTR amyloidogenesis is highly susceptible to water infiltration and that the high hydrostatic pressure causes denaturation of TTR mainly by promoting the entrance of water molecules into the protein cavities and thus affects the dissociation of the tetramer. , Meanwhile, a recent work suggested that mutations at A108 and T119 with large residues, e.g., A108W, A108 V, T119M, and T119W, increased the tetramer’s stability by filling the empty cavity at the interface . Therefore, we can confirm that water plays a role in driving the tetramer dissociation of TTR.…”