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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., (Copyright © 2023 Elsevier Inc. All rights reserved.)

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., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Monitoring early-stage β-amyloid (Aβ) dimerization is a formidable challenge for understanding neurological diseases. We compared β-sheet formation and histidine site-specific two-dimensional infrared (2D IR) spectroscopic signatures of Aβ dimers with different histidine states (δ; N δ1 -H, ε; N ε2 -H, or π; both protonated). Molecular dynamics (MD) simulations revealed that β-sheet formation is favored for the δδδ:δδδ and πππ:πππ tautomeric isomers showing strong couplings and frequent contacts between the central hydrophobic core and C-terminus compared with the εεε:εεε isomer. Characteristic blue-shifts in the 2D IR central bands were observed upon monomer-dimer transformation. The εεε:εεε dimer exhibited larger frequency shifts than δδδ:δδδ and πππ:πππ implying that the red-shift may have a correlation with N δ1 -H(δ) protonation. Our results support the tautomerization/protonation hypothesis that attributes Aβ misfolding to histidine tautomers as a possible primary initiator for Aβ aggregation and facilitates the application of histidine site-specific 2D IR spectroscopy for studying early-stage Aβ self-assembly.

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., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

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.

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., (Copyright © 2021 Elsevier B.V. All rights reserved.)

As an intrinsic origin cause, histidine behaviors play a critical role in protein misfolding processes. Generally, the English (H6R) mutation will disrupt H6 interactions. However, the structural properties of Aβ40 H6R and Aβ42 H6R under the complex influence of a histidine tautomeric effect and an H6R mutation remain unclear. Therefore, we performed a replica exchange molecular dynamics simulation to unveil such structural properties. Our result showed that the H6R substitute could promote the generation of β-sheet structures in comparison to the wild type. Three β-strand structure properties were observed in Aβ40 (rδδ), Aβ42 (rεε), Aβ42 (rεδ), and Aβ42 (rδδ) with β-sheet contents of 47.5%, 37.2%, 46.9%, and 38.6%, respectively, and the dominant conformational properties of Aβ40 (rδδ), Aβ42 (rεε), Aβ42 (rεδ), and Aβ42 (rδδ) had top conformational states of 86.0%, 73.2%, 67.0%, and 56.5%, respectively. Further analysis confirmed that R6 had different mechanisms for controlling the conformational features in Aβ40 H6R and Aβ42 H6R. In the Aβ40 systems, H14 H-bond networks played a critical role in controlling the structural properties. However, in the Aβ42 systems, R6 was more important because it was directly involved in the β-strand formation and maintained the β-sheet between the N-terminus and the central hydrophobic core region. Our current study helps to elucidate the histidine tautomeric behaviors in H6R mutations, which will present opportunities to understand the correlation between with/without H6 and the Aβ40/Aβ42 H6R misfolding mechanisms.

The accumulation of ΔK280 tau mutant resulting in neurotoxic oligomeric aggregates is an important but yet mysterious procedure in Alzheimer's disease (AD) development. Recently, we proposed a histidine tautomerization hypothesis of tau fibrillogenesis for the pathobiology of AD and other neuro diseases. However, the influence of neutral histidine tautomeric states on tau mutation is still unclear. Herein, we performed replica-exchange molecular dynamics (REMD) simulations to characterize structural features as well as the mode of toxic action of the ΔK280 tau mutant in the presence of histidine tautomerism. Molecular dynamics (MD) simulation results show that the δε tautomeric isomer (having a distinct global energy minimum) had the highest β-sheet structure, which adopts a sheet-rich conformer and may have significant influence on the structural behaviors of ΔK280 tau monomers. Furthermore, clustering, residual contact map, mobility and structural analysis exhibited that the presence of β-strand interactions between stable lysine 8 (K8)-asparagine 13 (N13) and valine 39 (V39)-tyrosine 43 (Y43) residues plus K31-histidine 32 (H32) and K8-N13 (strand-loop-strand [β-meander] structure) helped δε to form toxic aggregates. Moreover, H299 played a more critical role in the conformational instability of the δε than H268. Overall, the results obtained from this study may be used to arrest neurodegeneration in ΔK280 tau mutation carriers as well as increase the understanding of AD-related tau pathogenesis and strengthen the histidine tautomerism hypothesis of misfolded peptide accumulation.

Histidine tautomerism is considered a crucial component that affects the constitutional and accumulation characteristics of the tau 267-312 monomer in the neutral condition, which are connected with the pathobiology of Alzheimer's disease (AD). Interpreting the organizational characteristics and accumulation procedure is a challenging task because two tautomeric conformations (the N ε -H or N δ -H tautomer) can occur in the open neutral condition. In the current work, replica-exchange molecular dynamics (REMD) simulations were performed to investigate the structural properties of the tau 267-312 monomer considering the histidine tautomeric effect. Based on the simulation outcomes, the histidine 268 (H268) (δ)-H299 (δ) (δδ) isomer had the highest β-sheet content with a value of 26.2%, which acquires a sheet-governing toxic conformer with the first abundant conformational state of 22.6%. In addition, δδ displayed notable antiparallel β-sheets between lysine 8 (K8)-asparagine 13 (N13) and valine 40 (V40)-tyrosine 44 (Y44) as well as between K32-H33 and V40-Y44 (β-meander supersecondary structure), indicating this tautomeric isomer may exist to stimulate tau oligomerization. Furthermore, H299 was found to play an essential role in the structural stabilization of the δδ isomer compared with H268. The present research will aid in obtaining insight into the organizational and accumulation properties of tau protein in the presence of histidine tautomerism to control AD.

Histidine state (protonated or δ or ε tautomer) has been considered the origin of abnormal misfolding and aggregation of β-amyloid (Aβ). Our previous studies reported that the δδδ isomer of Aβ (1-40) has a greater propensity for β-sheet conformation compared to other isomers. However, direct proof of the tautomeric effect has not been reported. In this context, we calculated histidine site-specific two-dimensional infrared spectroscopy of the δδδ, εεε, and πππ (all protonated histidine) systems within the framework of classical molecular dynamics simulations aiming at connecting our previous results with the current experimental observations. Our results showed that β-sheet formation is favored for the δδδ and πππ tautomers compared with the εεε tautomer, consistent with our previous studies. This result was further supported by contact map analyses and the strength of dipole coupling between the amide-I bonds of each residue. The two-dimensional infrared diagonal trace for each tautomer included three distinctive spectrally resolvable peaks near 1680, 1686, and 1693 cm -1 , as was also observed for histidine dipeptides. However, the peak positions at His6, His13, and His14 did not show a consensus trend with the histidine or protonation state but were instead affected by the presence of surrounding hydrogen bonds. Our study provides a deeper insight into the influence of tautomerism and protonation of histidine residues in Aβ (1-40) on amyloid misfolding and provides a connection between our previous simulations and experimental observations., (Copyright © 2020 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

The self-assembly of amyloid-β (Aβ) peptides into senile plaques in the brain is a hallmark of Alzheimer's disease (AD) pathology. Mutation and histidine tautomerism are considered intrinsic origins in the accumulation of Aβ. As a first step toward understanding the impact of A2V mutation and histidine tautomerism on the Aβ42 isoform, we performed replica-exchange molecular dynamics (REMD) simulations to investigate the effects of histidine tautomerism on the structural properties of A2V Aβ42 peptides. There are generally more β-sheet and less α-helix secondary structures in A2V Aβ42 monomers than in WT Aβ42, implying a higher aggregation tendency in A2V Aβ42, which is consistent with previous studies. The current research will help develop the histidine tautomerism hypothesis of misfolded protein aggregation and eventually elucidate the pathogenesis of AD.

Many studies have focused on histidine behaviors in misfolding diseases. However, histidine behaviors on mature fibrils are still unknown. In the current study, we investigated mature fibrils with various histidine states to understand the structural properties of the histidine tautomeric effect on mature fibrils. Our results show that substituting chain 1 with different histidine states affects Aβ structural properties in A2, D7-G9, H14-Q15, S26-N27, and G33-G37 regions. The binding free energies with substituted fibrils were influenced not only along the axial direction, but also between duplex fibrils. Our results suggest that substituted (εδδ) preferentially disturbed the stability among the current mature fibrils. Further, H-bonded network differences indicate that twisted morphologies in mature fibrils are derived from the position and orientation of the imidazole ring in histidines. Our current study helps to elucidate histidine behaviors on mature fibrils, which will present opportunities to understand the misfolding mechanisms.

Mutation is considered an important factor in the accumulation of amyloid-β (Aβ), which is a hallmark of Alzheimer's disease (AD). A2V Aβ40 shows a higher aggregation tendency; however, the existing knowledge is not sufficient to explain the mechanism. We performed replica-exchange molecular dynamics simulations (REMD) to investigate the structural properties of A2V Aβ40 monomers and consider the tautomerism of histidine. The collective effects of the mutation and tautomerism leads A2V Aβ40 to much higher β-sheet and lower α-helix contents than WT Aβ40, which may explain the enhanced aggregation kinetics of A2V Aβ40 with respect to WT Aβ40. The current research provides new insights on understanding the pathology of AD.

As the intrinsic origin of the hypothesis for β-amyloid (Aβ) from Alzheimer's disease, histidine behaviors were found to play a crucial role in Aβ aggregation. To investigate the histidine behaviors during the early stage of aggregation, Aβ40/42 pentamers with different histidine isomer states were simulated at the atomic level. Results show that five Aβ40 (δδδ) and Aβ42 (εδδ) monomers can rapidly decrease the aggregation threshold, promote stable pentamer formation, and increase pentamer contents by 51.8% and 56.7%, respectively, as compared with the values of their wild-type (εεε) counterparts. Additionally, pentamers of Aβ40 (δδδ) and Aβ42 (εδδ) have different aggregation pathways and disassembly species, Tr+D and Te+M, during the growth of the pentamer. This work discloses the significance of histidine tautomerization in Aβ aggregation, implying a potential way to control Aβ aggregation and develop the assembly inhibitors.

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., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Tautomeric state of histidine is one of the factors that influence the structural and aggregation properties of amyloid β (Aβ)-peptide in neutral state. It is worth it to uncover the monomeric properties of Aβ(1-42) peptide in comparison with Aβ(1-40) peptide. Our replica-exchange molecular dynamics simulations results show that the sheet content of each tautomeric isomer in Aβ(1-42) monomer is slightly higher than that in Aβ(1-40) monomer except His6(δ)-His13(δ)-His14(δ) (δδδ) isomer, implying higher aggregation tendency in Aβ(1-42), which is in agreement with previous experimental and theoretical studies. Further analysis indicates that (εεε), (εδε), (εδδ), and (δδε) isomers prefer sheet conformation although they are in nondominating states. Particularly, it is confirmed that antiparallel β-sheets of (εδδ) were formed at K16-E22 (22.0-43.9%), N27-A30 except G29 (21.9-40.2%), and M35-I41 except G37 (24.1-43.4%). Furthermore, (εδδ) may be the easiest one to overcome structural transformation due to nonobstructing interactions between K16 and/or L17 and histidine residues. The current study will help to understand the tautomeric effect of Aβ(1-42) peptide to overcome Alzheimer's disease.

Histidine state (deprotonated, neutral, and protonated) is considered an important factor influencing the structural properties and aggregation mechanisms in amyloid β-peptides (Aβ), which are associated with the pathogenesis of Alzheimer's disease. Understanding the structural properties and aggregation mechanisms is a great challenge because two forms (the N ε -H or N δ -H tautomer) can exist in the free neutral state of histidine. Here, replica-exchange molecular dynamics simulation was performed to elucidate the changes in structure and the mechanism of aggregation influenced by tautomeric behaviors of histidine in Aβ(1-40). Our results show that sheet-dominating conformations can be found in the His6(δ)-His13(δ)-His14(δ) (δδδ) isomer with significant antiparallel sheet structures between R5-D7 and L34-G38, as well as between L17-F20 and L34-G38, implying that a new aggregation mechanism may exist to promote the generation of oligomers and/or aggregates. This work is helpful in understanding the fundamental tautomeric behaviors of neutral histidine in the process of aggregation.

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]