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Tautomeric Effect of Histidine on the Monomeric Structure of Amyloid #-Peptide(1-40) Hu Shi, Baotao Kang, and Jin Yong Lee J. Phys. Chem. B, Just Accepted Manuscript • DOI: 10.1021/acs.jpcb.6b08685 • Publication Date (Web): 17 Oct 2016 Downloaded from http://pubs.acs.org on October 20, 2016

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The Journal of Physical Chemistry

Tautomeric Effect of Histidine on the Monomeric Structure of Amyloid β-Peptide(1-40) Hu Shi†, Baotao Kang‡*, and Jin Yong Lee†* †

Department of Chemistry, Sungkyunkwan University, Suwon 440-746, Korea

‡

Department of Chemistry and Chemical Engineering, University of Jinan, Jinan 250022, P. R.

China

ABSTRACT: Histidine state (deprotonated, neutral, and protonated) is considered an important factor influencing the structural properties and aggregation mechanisms in amyloid β-peptides 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 Nε-H or NδH tautomer) can exist in the free neutral state of histidine. Here, replica exchange molecular dynamics simulation was performed to elucidate the changes of structure and mechanism of aggregation influenced by tautomeric behaviors of histidine in Aβ (1-40). Our results show that sheet dominating conformations can be found in His6(δ)-His13(δ)-His14(δ) (δδδ) isomer with significant antiparallel sheet structure between R5-D7 and L34-G38, as well as between L17-F20 and L34-G38, implying new aggregation mechanism may exist to promote oligomers and/or

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aggregates generation. This work is helpful for understanding the fundamental tautomeric behaviors of neutral histidine in the process of aggregation.

Introduction Alzheimer’s disease (AD), in which protein folding abnormalities is one of the pathogenic causes, is the most common form of dementia affecting more than 35 million people.1 It is pathologically characterized by progressive intracerebral accumulation of amyloid β-peptides (Aβ) and tau protein.2,

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The major component of plaques, Aβ fragments, are derived from

amyloid precursor protein (APP) by β- and γ-secretase proteolysis.4, 5 Approximately 90 % of the Aβ fragments generated are the 40 residue fragment (Aβ(1-40)).6,

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Aggregation of the

fragments, including toxic oligomers, plays a crucial role in the pathogenesis of AD.8-11 During Aβ aggregation, the “nucleated growth mechanism” has been accepted to describe the process of development from unfolded monomers to mature fibrils. That is, soluble and natively unfolded monomers first form β-structures, then generate the initial nucleus and proto-fibrils, and finally become mature fibrils.12,

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Many factors,14-17 such as pH environment, APP mutation, β-/γ-

secretase’s activity, and metal ions, can destroy the frail balance of Aβ production and clearance,18-21 and induce aggregation. Many literatures have focused on the effect of pH and researches have argued that small deviations in physiological pH can sensitively influence the chemical properties and aggregation tendency of Aβ peptides,22 which may be the reason why diseased brains are more acidic than the normal brain.23 The aggregation tendency is significantly high at pH 5 and 6.24 At pH 4 to 7, the β-sheet structure of Aβ(1-42), Aβ(1-28) and Aβ(1-39) is formed in aqueous


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trifluoroethanol.25 At pH 6, Aβ(1-28) and Aβ(10-42) folding are favorable for aggregation and are driven by hydrophobicity.26 Moreover, aggregation of Aβ(1-42) and shorter peptides is enhanced at pH 3.5 to 6.5.17 After reviewing these literatures, we determined that histidine is the only titratable amino acid with an uncertain condition.27 When in a protonated state, three protonated histidine residues promote the formation of β-sheet in Aβ(1-42) via a reduction in electrostatic repulsion between the two terminal regions,28 implying that the protonation states of histidine influence on peptide properties. However, regarding the unprotonated state, there is still a lack of studies on the effect of tautomeric state in neutral histidine residues in the full-length Aβ(1-40), although in N-AcAβ(13-23)NH2 monomer, only flexible folded structure was obtained in both unprotonated and protonated state of histidine.29. The imidazole side chain exists in two forms, the Nε-H tautomer (NεH, denoted as ε) and the Nδ-H tautomer (NδH, denoted as δ) (Scheme 1), and the population ratio of the two forms (ε/δ) is around 1:0.16.30-32 Tautomeric equilibrium occurs in picosecond.33 However, the population ratio of tautomeric isomers may significantly depend on environmental factors,34 such as histidine position (sequence number) and sidechain-sidechain interactions. Even a slight change in the surrounding physiological environment can perturb the population ratio of tautomeric isomers. Thus, a clear understanding of the tautomeric behavior of histidine residues in Aβ fragments is limited in experiment. However, tautomeric behaviors play an important role in the structural properties and aggregation mechanisms. In this context, we attempted to uncover how tautomeric behaviors effect the aggregation of Aβ by replica exchange molecular dynamics (REMD) simulations. Compared with standard molecular dynamics simulations, REMD is an enhanced sampling method that allows systems of similar potential energies to sample conformations at different temperatures.35


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Scheme 1. Tautomeric forms of histidine

The Aβ(1-40) monomer has three histidine residues located at position 6, 13, and 14 of the amino acid sequence. Each histidine has two tautomeric isomers (ε and δ), so there are eight isomers in the Aβ(1-40) monomer. The eight tautomeric isomers are denoted as (εεδ) in cases when the histidine residues are ε, ε, and δ isomers at amino acid positions 6, 13, and 14, respectively. Likewise, other isomers are denoted as (εεε), (εδε), (εδδ), (δεε), (δεδ), (δδε), and (δδδ) according to tautomeric forms. These isomers were investigated to obtain insight into the structural and aggregation features of Aβ(1-40). In order to determine if there is an influence of different force fields, compared with the ff99SB non-polarization force field in our REMD simulations, we employed the ff02 polarization force field for further standard MD simulation in (δδδ) and (εεε) isomers. Highly consistent ensembles (Figure S2) indicate that there is little dependence on the choice of force field. Furthermore, we added a 300 ns (δδε) simulation using (δδδ) secondary structure assignment as the initial structure. Spontaneous structural changes also supported our claim that configuration of the histidine residues is critical to the structural features (Figure S2).


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Simulation Details The crystal structure of the full-length Aβ(1-40) (PDB entry 1BA4), taken from the Protein Data Bank (http://www.rcsb.org/), was used in the present study. The eight tautomeric isomers were prepared by residual substitution with the Nε-H or Nδ-H tautomer at position number of 6, 13, and 14 of the amino acid sequence. The ff99SB non-polarization force field36 and implicit solvent generalized Born model were employed to perform the REMD simulations with the Amber 12/Amber14 package37. The AMBER ff99SB force field has been frequently used to simulate the proteins misfolding,38-40 which presents a careful reparametrization of the backbone torsion terms in ff99 and achieves a much better balance of four basic secondary structure elements.41 The SHAKE algorithm was applied to constrain the bonds including hydrogen. Particle mesh Ewald was used to describe the long-range electrostatics. The cutoff distance has an infinite value for non-bonded interactions. The temperature was controlled by the Langevin thermostat with coupling constants of 1.0 ps. The time step is 2.0 fs. Each simulation consisted of 10 replicas with the temperature range from 310 to 510 K. Exchanges between replicas were attempted every 4 ps. In the current simulations, more than 700 ns of data (each replica) were collected for each isomer. Our REMD results show that the acceptance ratio is ~22 %. Only the converged trajectories at 310 K were used to analyze the data. In addition, structural changes were exhibited using Visual Molecular Dynamics (VMD).42 We calculated the Pearson correlation coefficient (PCC) and Root-mean-square deviation (RMSD) (Table 1 in the main text) between our simulations and experimental data obtained from references (Ref. 55-57 in the main text). Our calculated 3JHNHA-coupling constants were derived from each converged trajectory using the Gromacs 5.043 analysis module. Coefficient values for the Karplus equation were 6.51, -1.76, and 1.60.44


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Results and Discussion

0.5 helix sheet

Probability

0.4 0.3 0.2 0.1 0.0 εεε

εεδ

εδε

εδδ

δεε

δεδ

δδε

δδδ

1.0 εεε εεδ εδε εδδ δεε δεδ δδε δδδ

0.8

Para

0.6 0.4 0.2 0.0 0

10

20

30

40

30

40

30

40

Residue 1.0 0.8

Anti

0.6 0.4 0.2 0.0 0

10

20

Residue 1.0 0.8

α-Helix

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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0.6 0.4 0.2 0.0 0

10

20

Residue

Figure 1. Probability distributions of averaged sheet and α-helix content in each isomer (A), and residual probability distributions of parallel β-sheet (B), antiparallel β-sheet (C), and α-Helix (D).


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After careful evaluation of convergence (Figure S1 and Table S1), the probability distributions of helix and sheet formation (Figure 1A) are remarkably different for eight isomers (details in Table S2), indicating that diverse neutral histidine tautomeric states (ε or δ) at sequence 6, 13, and 14 can dramatically influence the structural properties of Aβ(1-40). In particular, as the crucial secondary structural characteristics, the β-sheet content of (δδδ) (22.4 %) is much higher than that of other tautomeric states. As opposed to N-AcAβ(13-23)NH2 monomer that assumes a flexible folded structure,29 the (εεε) isomer exhibits ~49 % parallel β-bridge content in H6 and H14 (Figure 1B). In the (εδε) isomer, parallel β-bridge can be formed between Q15 and G38 with a probability of ~41 % (Figure 1B), while antiparallel β-bridge was generated between F20 and D23 with content of ~24 % (Figure 1C). Although the (εεε) and (εδε) isomers show significant chances to form β-bridge structures, these structures cannot further lead to formation of β-sheet. In contrast, antiparallel β-sheet can be found in the (δδδ) isomer, arising mostly between R5-D7 (content: 87 ~ 88 %) and L34-G38 (content: 37 ~ 90 %), and between L17-F20 (content: 39 ~ 88 %) and L34-G38 (Figure 1C). In the (δδδ) isomer, meanwhile, only E22-G33 exhibit marginal chances (< 29 %) to be involved in α-helical structures (Figure 1D). The observation of the dominant antiparallel β-sheet structure implies that the formation of the (δδδ) isomer may play a crucial role in Aβ oligomerization and/or aggregation because of the fatal structural transition from an individual soluble structure to a regular sheet structure.12, 45, 46


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Figure 2. Most abundant five conformational states and their probability distributions obtained by hierarchical agglomerative approach with cutoff of 5 Å via best-fit coordinate Root-mean-


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square deviation (RMSD) using alpha C atoms. Blue band represents L17-A21 region; green band represents sheet structure; blue sphere represents the N-terminus.

Based on cluster analysis, the (εεε) (δεδ), and (δδε) isomers were found to be unfolded or have a random propensity with significant structural diversity, which appear to be in a non-toxic state (Figure 2). Although a dominant structure was observed for the (εδε) isomer, the structure is rich in turn and coil structures rather than sheet or helix structures. Besides, owing to low sheet contents and high helix contents, the (εεδ), (εδδ), and (δεε) isomers also may not be toxic. It has been proposed that the toxicity of Aβ results from conformational transitions from α-helix or random coil to β-sheet structures.47 In contrast, the (δδδ) isomer is a β-sheet dominating conformer with 88.0 % of population based on cluster analysis (Figure 2). It is worth mentioning that the β-sheet structures occur in the N-terminus, the central L17-A21 region (recognition unit), and the C-terminal region. In particular, the β-sheet between the L17-A21 region and C-terminal region was reported as the intrinsic property in aggregation deposits. In this regard, the (δδδ) isomer could promote oligomers formation, and such oligomers may function as toxicity agents in the pathology of AD.11, 48, 49


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Figure 3. Most dominating conformer of (δδδ) isomer (A) analyzed by cluster analysis with same approach (describe in Figure 2) but using all atoms. Insert figure (B) shows hydrogen bond networks between strand regions. Contact map (C) of (δδδ) isomer based on Alpha C interaction (upper triangle) and residual sidechain interaction (lower triangle) analysis. In contact map, X and Y axis represent residue number index, color (Z axis) represents distance between X residual


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index and Y residual index. Region (a) and (b) show antiparallel β-sheet structures. Region (c) figure out sidechain interactions between R5, E11, H14, and Q15.

In order to understand the structural details of (δδδ) isomer, cluster analysis was employed using the same approach (above) but based on all atoms. The probability of the most abundant five conformational states were 54.1%, 11.7%, 8.1%, 6.4%, and 2.2%, respectively (Figure S3). The most dominant conformer is shown in Figure 3A. There is a tendency to adapt the antiparallel β-sheet between L17-V18 and V36-G38 (Figure 3C, upper triangle, (a)), which is in good agreement with the previous findings that the β-sheet primarily occurs at the CHC and Cterminus.50, 51 Meanwhile, another substantial antiparallel β-sheet character occurs between R5D7 and V36-G38 (Figure 3C, upper triangle, (b)). The same tendency was found between current study and previously reported studies that β-content can occur in N-terminus, especially, in the first six residues.52, 53 Ball et al. also reported the formation of two β-sheets in three β-strand structures from MD simulations: one β-sheet is between CHC and G9-H13, and the other one between CHC and residues M35-G37.54 To compare the present study with this previous study, (εεε) isomer was selected because ε isomer is the default histidine state in simulations. After analyzing 2384 frames of the (εεε) isomer (Figure S4), anti-parallel sheet was obtained in residues G9-H13, CHC, and residue S26-V39, which is consistent with the above findings. Additionally, in the (δδδ) isomer, exposure of the recognition unit (L17-A21 region) and charged residues implies that the (δδδ) isomer has ideal conditions as a potential seed to promote oligomers and/or aggregates generation. Moreover, the most commonly populated long-distance backbone hydrogen bonds between the CHC and the C-terminal regions reveal that L17/G37, V18/G18, and F19/M35 (Figure 3C, upper triangle, (a)) play an important role in the stability of


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the antiparallel β-sheet structure. Meanwhile, F4/V39, R5/G38, H6/G37, D7/V36, and S8/M35 (Figure 3C upper triangle, (b)) are crucial for the interaction between the N-terminal and Cterminal regions. In sidechain hydrogen bond networks (Figure 3B, and Figure 3C lower triangle, (c)), H14/E11, R5/E11, R5/V40, Q15/R5, and Q15/V40 hydrogen bonds were obtained. Compared with His6(δ) and His13(δ), we can see that His14(δ) plays an important role in the structural stability of (δδδ) via a hydrogen bond in H14/E11. In order to uncover the role of δ in (δδδ), (δδε), (δεδ), and (εδδ), the hydrogen bond population was collected in Table S3. In (δδδ), 44.90 % of the hydrogen bond population was obtained in E11/H14, and there was no interaction with H6 and H13. Compared with (δδδ), (δδε) lost the E11/H14 interaction, while interactions in Y10/H14, H14/L17, and H14/K16 were found due to substitution of ε for δ in residue 14. Interestingly, the interactions of L17 and K16 with H13 were detected in (δεδ) and (εδδ) with population range from 14.05 % to 16.10 %. Such backbone hydrogen bonds would obstruct the interaction between the central L17-A21 region and C-terminal region. This explains why (δδδ) shows antiparallel β-sheet feature while (δδε), (δεδ), and (εδδ) do not.

Table 1. Pearson correlation coefficient (PCC) and RMSD between our REMD calculated (Table S4) and experimental 3JHNHA-coupling constants.

εεε

with Ref. 55

with Ref. 56

with Ref. 57

PCC

RMSD(Hz)

PCC

RMSD(Hz)

PCC

RMSD(Hz)

0.44

0.97

0.44

0.97

0.54

0.72


12

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εεδ

-0.06

1.41

-0.09

1.21

0.40

0.82

εδε

0.16

1.38

-0.02

1.47

0.78

0.71

εδδ

0.01

1.24

0.11

1.08

0.62

0.70

δεε

0.13

1.59

0.17

1.56

0.58

0.67

δεδ

0.40

0.84

0.44

0.79

0.53

0.75

δδε

0.50

0.77

0.65

0.66

0.39

0.89

δδδ

0.30

1.07

0.28

0.97

0.48

0.80

PCC is derived from averaged 3JHNHA-coupling constant between simulated and experimental data. RMSD is standard deviation by calculating averaged deviation between simulated and experimental data.

Although it is too difficult to distinguish specific isomers in experiment, the ensemble of specific tautomeric state or mixed states should be in agreement with previous experimental data. In this regard, we calculated the PCC and RMSD (Table 1) between our simulations and experimental data obtained from references55-57. Compared with the experimental data in Ref. 55, maximum PCC of 0.50 with RMSD of 0.77 was located at the (δδε) isomer. When compared with Ref. 56, PCC changed into 0.65 with RMSD of 0.66, implying these experimental data are in agreement with the (δδε) isomer. Compared with Ref. 57, the PCC is 0.78 with RMSD of 0.71 for the Aβ(25-35) fragment, so we would conclude that the (εδε) isomer was preferred in Ref. 57. Significant combinations of the tautomeric behaviors of histidine could contribute to the


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diversity in experimental results which may be derived from different experimental conditions and environments. Up to now, the aggregation mechanisms influenced by the tautomeric state of histidine in Aβ(1-40) can be speculated out. The populations of Aβ(1-40) and Aβ(1-42) in human central nerve system are almost equivalent in both AD patients and normal humans. However, the rate of clearance is significantly reduced for AD patients.58 Considering that the tautomeric effect is a fundamental behavior in the free neutral histidine state, the (δδδ) isomer with rich sheet character would contribute to the pathway that produces Aβ oligomers and/or aggregates. In the nonpathogenic pathway, the production and clearance of Aβ pieces (monomers, oligomers, or aggregates) have a perfect balance for maintaining a normal healthy concentration of Aβ in the brain.59 However, in the pathogenic pathway, a weakened clearance (Apolipoprotein E4 inheritance, faulty Aβ degradation, etc60) destroys the frail balance, and induces the histopathological properties of AD. The present study proposes that the frail balance can be shifted by developing small molecules to inhibit the (δδδ) isomer.

Conclusion In summary, REMD simulations were carried out to investigate the structural properties and aggregation mechanisms of Aβ(1-40) under different tautomeric behaviors of histidine in the free neutral state. We found that different isomers display distinctly different compositions of secondary structures. Among eight isomers, the (εεε), (δεδ), and (δδε) isomers are structurally disordered in the absence of any dominant conformational features. The (εδε) isomer does have a dominant conformation that however is composed mainly of turn and coil structures. The (εεδ),


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(εδδ), and (δεε) isomers exhibit also dominant conformations with regular secondary structures but these structures are largely helical. Only the (δδδ) isomer could assume dominant conformations enriched with β-sheet structures. Secondary structure analysis, cluster analysis, and contact map suggested that these conformations are featured with antiparallel β-sheet between R5-D7 (content: 87 ~ 88 %) and L34-G38 (content: 37 ~ 90 %), as well as those between L17-F20 (content: 39 ~ 88 %) and L34-G38. Furthermore, we found that H14 plays an more important role in structural stability in the (δδδ) isomer as compared with H6 and H13. The interactions of each histidine with L17 and K16 play a critical role to different structural features of (δδε), (δεδ), and (εδδ) in comparison with (δδδ), since backbone hydrogen bonds would obstruct interactions between central L17-A21 region and C-terminal region. Together, our study argues for the tautomeric states of neutral histidine can influence the aggregation of Aβ(1-40), which would be useful for understanding the pathology of AD and design of drugs for therapeutic treatment. Our study opens a new avenue to the study of the effects of tautomerism of histidine in protein misfolding diseases.

ASSOCIATED CONTENT Supporting Information. Convergence details, secondary structure distributions in each isomer, structure properties of (δδδ) isomer in ff02 polarization force field, Hydrogen bond interaction, 3

JHNHA-coupling constant and standard deviation in each isomer.

AUTHOR INFORMATION Corresponding Author


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* Jin Yong Lee, Email: [email protected], Tel: +82-031-299-4560 * Baotao Kang, Email: [email protected], Tel: +86-0531-827605961 Notes The authors declare no competing financial interests.

ACKNOWLEDGMENT This work was supported by National Research Foundation (NRF) grants funded by the Ministry of Education, Science and Technology, subjected to the project EDISON (Education-research Integration through Simulation on the Net, Grant No.: 2012M3C1A6035359). KISTI supercomputing center through the strategic support program for the supercomputing application research [No. KSC-2014-C2-056].

ABBREVIATIONS AD, Alzheimer’s disease; Aβ peptides, amyloid β-peptides; REMD, replica exchange molecular dynamics; RMSD, Root-mean-square deviation; PCC, Pearson correlation coefficient.

REFERENCES 1. Goedert, M.; Spillantini, M. G. A century of Alzheimer's disease. Science 2006, 314, 777-781. 2. Hardy, J.; Selkoe, D. J. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 2002, 297, 353-356.


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Tautomeric Effect of Histidine on the Monomeric ... - ACS Publications

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