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Aggregation of profilin-1 (PFN1) causes a fatal neurodegenerative disease, familial amyotrophic lateral sclerosis (fALS). Histidine (His) tautomerism has been linked to the formation of fibril aggregation causing neurodegenerative disease. Characterization of intermediate species that form during aggregation is crucial, however, this has proven very challenging for experimentalists due to their transient nature. Hence, molecular dynamics (MD) simulations have been performed on the His tautomeric isomers εε, εδ, δε, and δδ of PFN1 to explain the structural changes and to correlate them with its aggregation propensity. MD simulations show that His133 presumably plays a major role in the aggregation of PFN1 upon His tautomerism compared to His119. Further, the formation of a new 3 10 -helix is observed in εε and δε but 3 10 -helix is not observed in δδ and εδ isomers. In addition, our findings unveil that β-sheet dominating conformations are observed in His119(δ)-His133(δ) δδ isomer of PFN1 with significant antiparallel β-sheets between residues T15-G23, S29-A33, L63-L65, Q68-S76, F83-T89, T97-T105, and K107-K115, suggesting a novel aggregation mechanism possibly occur for the formation of PFN1 aggregates. Overall, these results propose that MD simulations of PFN1 His tautomers can provide a detailed microscopic understanding of the aggregation mechanisms which are hard to probe through experiments. [ABSTRACT FROM AUTHOR]

The intrinsic origin of amyloid aggregation has been pursued as a new pathogenesis for Alzheimer's disease (AD). The aggregation mechanisms influenced by histidine tautomerism were previously investigated in Aβ40 and Aβ42 monomers. In the present study, we focus on the structural properties of Aβ40 heterodimer under the influence of histidine. The results of molecular dynamics simulation detected different aggregation trends were detected in different heterodimers formed by the εεε isomer and other isomers. In the (εεε:δδδ) dimer, the highest β‐sheet content was obtained in the δδδ chain, which is in agreement with our previous studies that δδδ monomer is the most easily formed β‐sheet secondary structure in the monomer. Further analysis confirmed that (εεε:δδδ) dimers more easily aggregate into fibrils in comparison with other heterodimers. This research will help in understanding the tautomeric effect on Aβ heterodimers, thereby helping to figure out the pathogenesis of AD. [ABSTRACT FROM AUTHOR]

Mutations and histidine (His) tautomerism in profilin-1 (PFN1) are associated with amyotrophic lateral sclerosis (ALS). The conformational changes in PFN1 caused by the collective effects of G117V mutation and His tautomeric isomers εε, εδ, δε, and δδ were clarified using molecular dynamics (MD) simulations. The predominant structural variations were seen in α-helices, β-sheets, turns, and coils and the His tautomer's unique degree of disruption was seen in these conformations. The content of α-helices was 23.2 % in the εε and δδ isomers, but the observed α-helices in the isomers εδ and δε were 20.3 % and 21.7 % respectively. The percentage of β-sheet was found to be higher (34.1) in the εε isomer than in the εδ, δε, and δδ isomers, and the values were 30.4, 29.7, and 31.9, respectively. Intermolecular water dynamics analysis discloses that His 133 can form an intramolecular H-bond interaction (Nα-H---Nδ), confirming the experimental observations in the simulations of εε, δε, and δδ isomers of G117V PFN1 mutant. It was concluded that these solvent molecules are crucial for aggregation and must be considered in future research on the PFN1 associated with ALS. Overall, the study offers a thorough microscopic understanding of the pathogenic mechanisms behind conformational changes that cause aggregation illnesses like ALS. [ABSTRACT FROM AUTHOR]

Hundreds of millions of people around the world have been affected by Type 2 diabetes (T2D) which is a metabolic disorder. Clinical research has revealed T2D as a possible risk factor for Alzheimer's disease (AD) development (and vice versa). Amyloid-β (Aβ) and human islet amyloid polypeptide are the main pathological species in AD and T2D, respectively. However, the mechanisms by which these two amyloidogenic peptides co-aggregate are largely uninvestigated. Herein, for the first time, we present the cross-seeding between Amylin1-37 and Aβ40 considering the particular effect of the histidine tautomerism at atomic resolution applying the all-atom molecular dynamics (MD) simulations for heterodimeric complexes. The results via random seed MD simulations indicated that the Aβ40(δδδ) isomer in cross-talking with Islet(ε) and Islet(δ) isomers could retain or increase the β-sheet content in its structure that may make it more prone to further aggregation and exhibit higher toxicity. The other tautomeric isomers which initially did not have a β-sheet structure in their monomeric forms did not show any generated β-sheet, except for one seed of the Islet(ε) and Aβ40(εεε) heterodimers complex that displayed a small amount of formed β-sheet. This computational research may provide a different point of view to examine all possible parameters that may contribute to the development of AD and T2D and provide a better understanding of the pathological link between these two severe diseases. [ABSTRACT FROM AUTHOR]

Aggregated amyloid β-peptide (Aβ) in small oligomeric forms inside the brain causes synaptic function disruption and the development of Alzheimer's disease (AD). Histidine is an important amino acid that may lead to structural changes. Aβ42 monomer chain includes 3 histidine residues that considering two ε and δ tautomers 8 isomers, including (εεε) and (εδδ) could be formed. Molecular dynamics simulation on homodimerization of (εεε) (the most common type of tautomers) and (εδδ) tautomers with different initial configurations using monomer chains from our previous work were performed to uncover the tautomeric behavior of histidine on Aβ42 aggregation in a physiological pH which is still largely unknown and impossible to observe experimentally. We found a higher propensity of forming β-sheet in (εδδ) homodimers and specifically in a greater amount from Aβ42 than from Aβ40. A smaller amount of β-sheet formation was observed for (εεε) homodimers compared with (εδδ). Additionally, interactions in (εδδ) homodimers may indicate the importance of the hydrophobic core and C-/N-terminals during oligomerization. Our findings indicate the important role of the tautomeric effect of histidine and (εδδ) homodimers at the early stage of Aβ aggregation. • (εδδ) tautomers show a high propensity to generate β-sheets during homodimerization. • (εδδ) homodimers may play an important role at the early stage of Aβ aggregation. • Histidine tautomerism can affect the structural properties of the amyloid peptides. [ABSTRACT FROM AUTHOR]

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; N δ1 H and ε; N ε2 H) 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. [Display omitted] • Histidine tautomerism can influence the structural and misfolding properties of the monomeric TTR (26−57). • δδ and εδ tautomeric isomers are more likely to form β-sheets than εε and δε. • A potent therapeutic strategy for TTR amyloidosis may be to target toxic tautomeric states. • This study will help in developing effective therapeutic agents for the treatment of TTR-related amyloid diseases. [ABSTRACT FROM AUTHOR]

Controlling protein misfolding and accumulation in neurodegeneration is a challenge in chemical neuroscience. The application of appropriate electric fields (EFs) can be a potential noninvasive therapy to treat neuro disorders. The effect of EFs of varying intensities and directions on the conformational dynamics of β-Amyloid40 (Aβ40) under histidine tautomerism has been investigated for the first time. Our findings suggest that peptides tend to align their dipole moments with the orientation of EF. Irrespective of the EF direction, the dipole moment magnitude is affected by the EF strength. With the conformational changes, the EF strength equal to 0.5 V/nm destroyed the β-sheet content of the δδδ isomer as a potentially toxic agent. The content of the alpha-helical structure which can be transformed into the β-sheet is reduced. The strength of the EF showed a significant influence on the reduction of the number of intra-protein hydrogen bonds especially when EF is equal to 0.5 V/nm which could facilitate destabilization of the structure of the peptides. Current findings provide quantitative insights into the tautomerization-mediated Aβ40 dynamic and conformational changes induced by the external EFs in aqueous solutions, which may provide beneficial information for use as a therapeutic technique. • We explored the combined effect of an external EF and histidine tautomerism on the misfolding of monomeric Aβ40. • When EF = 0.5 V/nm was applied the β-sheet structure of the δδδ isomer was destroyed. • This work can be helpful for studying EF dependency structural changes in the presence of the tautomeric states. [ABSTRACT FROM AUTHOR]

Abstract Amyloid-beta protein (Aβ) accumulation in the brain, which is influenced by several factors, is a hallmark of Alzheimer's disease (AD). Despite the important role of histidine in stabilizing the fibrillar structure of the Aβ peptide at neutral pH, the effect of histidine tautomerism on Aβ peptide aggregation is still largely unknown. Histidine is in equilibrium between δ and ε tautomers and there are three histidine residues (H6, H13, and H14) in the Aβ(1–40) peptide. We performed molecular dynamics simulation on (δδδ) and (εεε) histidine tautomers with different initial homodimeric configurations to elucidate structural and aggregation features. Results indicate that (εεε) homodimers have very low propensity or almost no tendency to form β-sheets, whereas (δδδ) dimers predominantly form β-sheets due to interactions between central hydrophobic core (CHC) residues and C-terminal residues. β-sheet formation occurred in the same regions of each dimer chain at the CHC and C-/N- terminals for different configurations of (δδδ). These results suggest that (δδδ) has an important role in AD progression. Our study provides deeper insight into the effect of tautomerism of histidine residues in Aβ(1–40) on amyloid aggregation. Graphical abstract Unlabelled Image Highlights • (εεε) tautomers show low propensity to form β-sheets during homodimerization. • (δδδ) tautomers show high β-sheets amount during homodimerization. • (δδδ) tautomers may play more important role than (εεε) in Alzheimer. [ABSTRACT FROM AUTHOR]