Figure 4 - available via license: Creative Commons Attribution 4.0 International
Content may be subject to copyright.
Implied relaxation time scales of the constructed Markov state model (MSM) as a function of lag time.
Source publication
Misfolding and aggregation of transthyretin (TTR) is widely known to be responsible for a progressive systemic disorder called amyloid transthyretin (ATTR) amyloidosis. Studies suggest that TTR aggregation is initiated by a rate-limiting dissociation of the homo-tetramer into its monomers, which can rapidly misfold and self-assemble into amyloid fi...
Contexts in source publication
Context 1
... resulting MSM with 200 microstates was obtained using the k-means clustering method as described earlier. To validate the Markovian property of the obtained MSM, the implied time scales as a function of the lag time was first plotted; see Figure 4. Clearly, the implied time scale curves level off at lag time around 3 ns, suggesting the convergence of implied time scales with 200 microstates. ...
Context 2
... C-K test was performed using the cktest function in the PyEMMA software [46]. According to the plotted relaxation time scales shown in Figure 4, there were four slow processes separated from others, therefore the C-K test was performed with 5 macrostates and lag time of 3 ns. As shown in Figure S1, the C-K curves estimated from original simulations (black curves) matched quite well with the predicted ones (blue curves) from the constructed MSM, indicating that our constructed MSM is indeed Markovian. ...
Citations
... where T(τ) is the transition probability matrix with selected lag time τ and n is an integer number of steps. 74 The C−K compares MD trajectories at increasing time steps to the probability of the protein remaining in a specific state predicted by the constructed MSM. The MSM-reweighted free energy surface (FES) along the first two PC dimensions was also computed. ...
... It was previously shown that the TTR (105-115) peptide originating from the β-stand G is highly amyloidogenic (Gustavsson et al., 1991). A recent MD study reported a consistent result in which destabilization of the edge at the DAGH β-sheet, namely the β-stands D and H, is responsible for the amyloidogenic propensity of TTR (Zhou et al., 2019;Childers and Daggett, 2020). Furthermore, a series of computational studies have suggested that the DAGH β-sheet may experience structural deformation to reconstruct aggregation-prone α-sheet-like structures (Steward et al., 2008;Childers and Daggett, 2019). ...
Monomer dissociation and subsequent misfolding of the transthyretin (TTR) is one of the
most critical causative factors of TTR amyloidosis. TTR amyloidosis causes several human diseases, such as senile systemic amyloidosis and familial amyloid cardiomyopathy/polyneuropathy; therefore, it is important to understand the molecular details of the
structural deformation and aggregation mechanisms of TTR. However, such molecular
characteristics are still elusive because of the complicated structural heterogeneity of TTR
and its highly sensitive nature to various environmental factors. Several nuclear magnetic
resonance (NMR) spectroscopy and molecular dynamics (MD) studies of TTR variants
have recently reported evidence of transient aggregation-prone structural states of TTR.
According to these studies, the stability of the DAGH β-sheet, one of the two main β-sheets
in TTR, is a crucial determinant of the TTR amyloidosis mechanism. In addition, its
conformational perturbation and possible involvement of nearby structural motifs
facilitates TTR aggregation. This study proposes aggregation-prone structural
ensembles of TTR obtained by MD simulation with enhanced sampling and a multiple
linear regression approach. This method provides plausible structural models that are
composed of ensemble structures consistent with NMR chemical shift data. This study
validated the ensemble models with experimental data obtained from circular dichroism
(CD) spectroscopy and NMR order parameter analysis. In addition, our results suggest that
the structural deformation of the DAGH β-sheet and the AB loop regions may correlate with
the manifestation of the aggregation-prone conformational states of TTR. In summary, our
method employing MD techniques to extend the structural ensembles from NMR
experimental data analysis may provide new opportunities to investigate various
transient yet important structural states of amyloidogenic proteins.
... It was previously shown that the TTR (105-115) peptide originating from the β-stand G is highly amyloidogenic (Gustavsson et al., 1991). A recent MD study reported a consistent result in which destabilization of the edge at the DAGH β-sheet, namely the β-stands D and H, is responsible for the amyloidogenic propensity of TTR (Zhou et al., 2019;Childers and Daggett, 2020). Furthermore, a series of computational studies have suggested that the DAGH β-sheet may experience structural deformation to reconstruct aggregation-prone α-sheet-like structures (Steward et al., 2008;Childers and Daggett, 2019). ...
Monomer dissociation and subsequent misfolding of the transthyretin (TTR) is one of the most critical causative factors of TTR amyloidosis. TTR amyloidosis causes several human diseases, such as senile systemic amyloidosis and familial amyloid cardiomyopathy/polyneuropathy; therefore, it is important to understand the molecular details of the structural deformation and aggregation mechanisms of TTR. However, such molecular characteristics are still elusive because of the complicated structural heterogeneity of TTR and its highly sensitive nature to various environmental factors. Several nuclear magnetic resonance (NMR) spectroscopy and molecular dynamics (MD) studies of TTR variants have recently reported evidence of transient aggregation-prone structural states of TTR. According to these studies, the stability of the DAGH β-sheet, one of the two main β-sheets in TTR, is a crucial determinant of the TTR amyloidosis mechanism. In addition, its conformational perturbation and possible involvement of nearby structural motifs facilitates TTR aggregation. This study proposes aggregation-prone structural ensembles of TTR obtained by MD simulation with enhanced sampling and a multiple linear regression approach. This method provides plausible structural models that are composed of ensemble structures consistent with NMR chemical shift data. This study validated the ensemble models with experimental data obtained from circular dichroism (CD) spectroscopy and NMR order parameter analysis. In addition, our results suggest that the structural deformation of the DAGH β-sheet and the AB loop regions may correlate with the manifestation of the aggregation-prone conformational states of TTR. In summary, our method employing MD techniques to extend the structural ensembles from NMR experimental data analysis may provide new opportunities to investigate various transient yet important structural states of amyloidogenic proteins.
... The most relevant compounds are listed in Table 1 and will be discussed in the following sections. In the recent years, computational studies, such as molecular dynamics (MD) simulations, molecular docking and quantitative structural-activity relationships (SAR) have been used as complement of experimental approaches to better understand TTR monomer misfolding mechanismsdriving TTR amyloidogenesis (Zhou et al., 2019), as well as the binding of small molecules to TTR (Dessi et al., 2020). Indeed, these in silico experiments have been essential to obtain a more detailed information about structural changes in biomolecules and, have been used to determine the structural dynamics of TTR (Ortore and Martinelli, 2012;Zhao and Lei, 2014), which in turn will be particularly relevant to the development of more targeted and effective therapies for the treatment of ATTR amyloidosis. ...
Transthyretin (TTR) amyloidoses are systemic diseases associated with TTR aggregation and extracellular deposition in tissues as amyloid. The most frequent and severe forms of the disease are hereditary and associated with amino acid substitutions in the protein due to single point mutations in the TTR gene (ATTRv amyloidosis). However, the wild type TTR (TTR wt) has an intrinsic amyloidogenic potential that, in particular altered physiologic conditions and aging, leads to TTR aggregation in people over 80 years old being responsible for the non-hereditary ATTRwt amyloidosis. In normal physiologic conditions TTR wt occurs as a tetramer of identical subunits forming a central hydrophobic channel where small molecules can bind as is the case of the natural ligand thyroxine (T 4 ). However, the TTR amyloidogenic variants present decreased stability, and in particular conditions, dissociate into partially misfolded monomers that aggregate and polymerize as amyloid fibrils. Therefore, therapeutic strategies for these amyloidoses may target different steps in the disease process such as decrease of variant TTR (TTRv) in plasma, stabilization of TTR, inhibition of TTR aggregation and polymerization or disruption of the preformed fibrils. While strategies aiming decrease of the mutated TTR involve mainly genetic approaches, either by liver transplant or the more recent technologies using specific oligonucleotides or silencing RNA, the other steps of the amyloidogenic cascade might be impaired by pharmacologic compounds, namely, TTR stabilizers, inhibitors of aggregation and amyloid disruptors. Modulation of different steps involved in the mechanism of ATTR amyloidosis and compounds proposed as pharmacologic agents to treat TTR amyloidosis will be reviewed and discussed.
Characterization of the conformational alterations involved in monomer misfolding is essential for elucidating the molecular basis of the initial stage of protein accumulation. Here, we report the first structural analyses of transthyretin (TTR) (26-57) fragments with two histidine tautomeric states (δ; Nδ1H and ε; Nε2H) using replica-exchange molecular dynamics (REMD) simulations. Explaining the organizational properties and misfolding procedure is challenging because the δ and ε configurations can occur in the free neutral state. REMD revealed that β-sheet generation is favored for the δδ (16.8%) and εδ (6.7%) tautomeric isomers, showing frequent main-chain contacts between the stable regions near the head (N-terminus) and central (middle) part compared to the εε (4.8%) and δε (2.8%) isomers. The presence of smaller and wider local energy minima may be related to the structural stability and toxicity of δδ/εδ and εε/δε. Histidines31 and 56 were the parts of regular (such as β-strand) and nonregular (such as coil) secondary structures within the highly toxic TTR isomer. For TTR amyloidosis, focusing on hazardous isomeric forms with high sheet contents may be a potent treatment strategy. Overall, our findings support the tautomerism concept and aid in our comprehension of the basic tautomeric actions of neutral histidine throughout the misfolding process.
