Research Article pubs.acs.org/chemneuro
Tautomeric Effect of Histidine on the Monomeric Structure of Amyloid β‑Peptide(1−42) Hu Shi and Jin Yong Lee* Department of Chemistry, Sungkyunkwan University, Suwon 440-746, Korea S Supporting Information *
ABSTRACT: 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. KEYWORDS: Tautomeric effect, amyloid(1−42) peptide, histidine tautomer, sheet structure, protein misfolding, aggregation dramatically figured out after a large number of experimental and computational studies. In fibrils, Aβ(1−40) and Aβ(1−42) kept highly similar morphologies with β-strand orthogonal to the axis of fibril, which were stable by intramolecular and intermolecular interactions between β-strands.15−18 In monomeric conformation, different features have been reported. Some studies reported that Aβ(1−40) adopted β-hairpin with substantial proclivity between central hydrophobic cluster (CHC, L17-A21) and A30-V36,19,20 However, Aβ(1−42) showed three antiparallel β-strand in CHC, A30-V36, and V39−I41.20−22 Some studies figured out β-hairpins can be found in Aβ(1−42) but not/less in Aβ(1−40).23−26 The same tendency is that Aβ(1−42) has higher propensity to adopt sheet conformation than Aβ(1−40) under the same environment condition. The balance between Aβ production and clearance has been suggested to understand the accumulation procedure of senile plaques. If Aβ production is equal to or less than Aβ clearance, there is no absolute accumulation. Otherwise, absolute accumulation of Aβ production will promote the generation of senile plaques.27,28 However, many factors, such as pH environment, APP mutation, β-/γ-secretase activity, and metal ions, can affect such frail balance.29−32 Recently, proper chemical tools
A
lzheimer’s disease (AD) is the most common form of dementia,1 which is one of misfolding diseases without effective treatments to date. The characteristic histopathological properties of AD are deposits of senile plaques (main component: amyloid β (Aβ) -peptide fragments) and entanglement of tau-protein.2 Aβ fragments are mainly 39−43 residues, which are derived from the amyloid precursor protein (APP) by β- and γ-secretase proteolysis.3,4 The content of Aβ fragment amino acid from 1 to 40 (Aβ(1−40)) was reported to exist 90%, and that of Aβ fragment amino acid from 1 to 42 (Aβ(1−42)) is 10%.5−7 Abnormal changes in APP and γ-secretase are critical to curious pathogenicity of the Aβ(1−42)/Aβ(1−40) ratio.8−10 Compared with Aβ(1−40), Aβ(1−42) has same primary amino acids from residue D1 to V40. The difference is that only two additional hydrophobic residues I41 and A42 appeared in the C-terminus of Aβ(1−42). Despite such a slight difference, Aβ(1−42) has been shown to be not only higher propensity to form aggregates and fibrils, but also extensive damage to neuronal cell.11,12 These phenomena indicate that two hydrophobic residues in C-terminus can significantly influence the structural properties between Aβ(1−40) and Aβ(1−42), which was confirmed by the distinct mechanism of oligomerization procedure.13,14 Monomeric forms of Aβ have been classified as intrinsically disordered peptides (IDPs), implying that there is diverse set of conformational states with native nondominant folded structures. However, similar structural morphologies were © XXXX American Chemical Society
Received: November 3, 2016 Accepted: November 16, 2016 Published: November 16, 2016 A
DOI: 10.1021/acschemneuro.6b00375 ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
Research Article
ACS Chemical Neuroscience were obtained to identify pathological factors, such as metals, Aβ, metal-Aβ, reactive oxygen species, and free organic radicals.33 In environment factor, many studies have confirmed that slight acidic condition can promote β-sheet formation and aggregation tendency.34−38 In Aβ peptides, contrary to other titratable amino acids, histidine residue is in uncertain condition (tautomer state).39 In the unprotonated state, the imidazole side chain of histidine exists in two forms, Nε−H tautomer (NεH, denoted as ε) and Nδ−H tautomer (NδH, denoted as δ), and the population ratio (ε/δ) was reported to be around 1:0.16.40−42 Moreover, the slightly environmental change can affect the probabilities of ε/δ. Therefore, the structural features of specific combination by ε and/or δ isomers of histidine residues cannot be elucidated in experiment, in this case, computational dynamics simulation would be an appropriate way to understand the tautomeric effect of histidine residues. In particular, the structural properties of Aβ peptides under specific ε and δ combination were hardly known. In Aβ fragment study, only flexible folded structure was obtained in monomeric N-AcAβ(13−23)NH2.43 In Aβ full-length study, our previous monomeric Aβ(1−40) study suggested that structural properties can be influenced by diverse ε and δ combinations. (δδδ) (δ isomer located at H6, H13, and H14 positions) adopts dominating three β-strands formation with interactions between R5-D7 and L34-G38, and L17-F20 and L34-G38.44 Theoretically, the transition between ε and δ isomer states of histidine is fast than misfolding procedure of peptide. However, transition is sensitive to environment conditions. Up to now, it is still unclear because Aβ is part of a class of intrinsically disordered proteins. So, it is worth studying the tautomeric effect on the aggregation of Aβ. We also reported that whether L17 and/or K16 hydrogen bond interaction with histidine residues is the key phenomenon which may imply that such hydrogen bond interaction may obstruct interaction between central L17-A21 region and C-terminal region. It is interesting to compare the structural features of Aβ(1−42) in comparison with Aβ(1−40) because Aβ(1−42) has a dramatically higher propensity to form fibrils and is known to cause serious toxicity to neurons than Aβ(1−40).11,12 In this regard, we tried to uncover the tautomeric effect on the monomeric Aβ(1−42) by replica-exchange molecular dynamics (REMD) simulations. Compared with standard molecular dynamics simulation, REMD is an enhanced sampling method by allowing systems of similar potential energies to sample conformations at different temperatures. Our current study is helpful in understanding self-assembly processes of Aβ in etiology of AD.
Figure 1. Sheet content of monomeric Aβ(1−42) in each isomer as compared with Aβ(1−40). Sheet content of Aβ(1−40) is obtained from ref 44. Error is the standard deviation which is derived from averaged data by calculating every 10 ns.
Aβ(1−42) monomer, we cited sheet content of Aβ(1−40) monomer in Figure 1. It is clearly shown that the sheet content of Aβ(1−42) monomer is generally higher than that of Aβ(1−40) monomer in each isomer except for (δδδ) isomer. It is worth to mention that ε formation is more abundant than δ formation under ideal neutral condition.40−42 Thus, we may conclude that the sheet content of Aβ(1−42) is generally higher than that of Aβ(1−40) in real mixed condition. This conclusion is in agreement with the fact that Aβ(1−42) has higher tendency to form sheet structure than Aβ(1−40) in both experimental and theoretical studies.46−48 In Aβ(1−40) monomer, (δδδ) isomer resulted in the highest sheet content.44 However, in Aβ(1−42) monomer, (εδδ) isomer exhibited the highest sheet content of 15.7%. The order of sheet content in Aβ(1−42) monomer was (εδδ) > (εδε) > (εεε) > (δδε) > (δεε) > (δεδ) > (δδδ) > (εεδ) with content of 15.7%, 7.0%, 6.5%, 5.4%, 5.2%, 4.6%, 4.2%, and 3.9%, respectively. In order to evaluate structural properties in Aβ(1−42) monomer, partial secondary structure (all of the data given in Table S2) of each isomer is collected in Figure 2. Despite high content parallel β-bridge between H6 and H13 (50.6%) in (εεε) isomer and high content antiparallel β-bridge between H6 and V36 (80.9%) in (δδδ) isomer, these isomers may not be crucial to the aggregation of Aβ(1−42) monomer because of low sheet content and no further folding. In contrast, in (εδδ) isomer, antiparallel β-sheets can be found in K16-E22 (22.0− 43.9%), N27-A30 expect G29 (21.9−40.2%), and M35-I41 except G37 (24.1−43.4%). Meanwhile, α-helix is located at K16-E22 with content of 13.1−22.5%, at N27-A30 with content of 3.2−4.2%, and at M35-I41 with content of 0.4−8.2%. However, in (εεε) isomer, a slight difference is that antiparallel β-sheet occurs at L17-A21 (1.6−17.0%), A30-V36 (2.0− 11.3%), and V39−I41 (12.4−19.8%). The structural features of (εεε) isomer is in agreement with previous studies,20−22 because ε isomer was often used as default isomer of histidine in normal molecular simulations. Similarly, in (δδε) isomer, antiparallel β-sheet can be found in K17-A21 (6.6−16.4%), G33-V36 (5.9−14.9%), and V39−I41 (9.6−13.2%). To the contrary, in (εδε) isomer, antiparallel β-sheet appears in E3-H6 (4.8−19.4%), V18-D23 (7.2−17.1%), and G33-I41 (4.8−21.3%). The difference is that β-sheet was obtained in N-terminus. Moreover, different to antiparallel β-sheet, in (δεδ) isomer, parallel β-sheet occurs at E11-K16 (content: 5.8−13.5%) and V36−I41 (content: 2.4−15.5%). There results demonstrate
■
RESULTS AND DISCUSSION More than 800 ns simulation per replica and more than 8 μs per combinatorial isomer were collected in current study. Our REMD acceptance ratio is 20−22%. After carefully evaluating the convergence (Figure S1 and Table S1), only the converged trajectories under 310 K were used to analyze the data. Structures were displayed using visual molecular dynamics package.45 It was known that the content of sheet formation of Aβ peptides is critical to form oligomers and fibrils from native state. With regard to that, the sheet formation content of each isomer is collected in Figure 1. One can easily find that sheet contents were dramatically different in 8 isomers of Aβ(1−42) monomer, which is similar to Aβ(1−40) monomer,44 implying that tautomeric effect of histidine can influence structural and aggregation properties of Aβ peptides. In order to easily compare the sheet content between Aβ(1−40) monomer and B
DOI: 10.1021/acschemneuro.6b00375 ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
Research Article
ACS Chemical Neuroscience
Figure 3. Most abundant five conformational states and their probability distributions obtained by a hierarchical agglomerative approach with a cutoff of 5 Å via best-fit coordinate root-mean-square deviation (RMSD) using α C atoms. The blue band represents the L17-A21 region, the green band represents the sheet structure, and the blue sphere represents the N-terminus.
Figure 2. Parallel-sheet (A), antiparallel sheet (B), and α-helix (C) content in each isomer. Error bar was derived from each 10 ns fragmental trajectory.
that difference isomers exhibited significantly various features of sheet structure location. Most abundant five conformational states and their probability distributions are collected in Figure 3. Different to sheetrich properties of (δδδ) isomer in Aβ(1−40) monomer, current (δδδ) isomer of Aβ(1−42) monomer adopts a helixdominating conformer with S1 (Most abundant conformation state 1) of 90.5%. Such a helix-dominating isomer may not be toxic because toxicity is presumed to be emerged under conformational switching from α-helix or random coil to sheet formation.49 In contrast, the rest of them preferred nondominating structures with significant structural diversity. The content of S1 in (εεε), (εεδ), (εδε), (εδδ), (δεε), (δεδ), and (δδε) are 6.5%, 2.3%, 6.9%, 10.3%, 7.1%, 3.4%, and 3.9%, respectively. Interestingly, although these are diverse conformations, (εεε), (εδε), (εδδ), and (δδε) (Figure S2 by cluster analysis on the basis of all atom) show higher sheet content as compared with (εεδ), (δεε), and (δεδ).
To evaluate the roles of histidine in (εεε), (εδε), (εδδ), and (δδε) isomers, hydrogen bond populations related to histidine residue were collected in Table S3. One can easily find out K16 and L17 interact with H13 in (εεε) isomer with content range from 13.92% to 29.19%. Such backbone hydrogen bonds were also found in Aβ(1−40) monomer study, which would intervene the interaction between central L17-A21 region and C-terminal region. Remarkably, such specific hydrogen bond interactions were also obtained in (εδε) (content: 5.43− 7.16%), and (δδε) (content: 6.04−7.68%). Therefore, one can conclude that (εδδ) isomer without such intervening interaction seems to most easily form regular sheet structures than any other isomers. Despite IDP phenomena were obtained in (εεε), (εδε), (εδδ), and (δδε) isomers, in order to further uncover structural properties, STRIDE algorithm was employed to select sheet C
DOI: 10.1021/acschemneuro.6b00375 ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
Research Article
ACS Chemical Neuroscience
Figure 4. Secondary structure properties and contact map in selected sheet component in (εεε), (εδε), (εδδ), and (δδε) isomers. Contact map was obtained on the basis of α C interaction. In the contact map, the X- and Y-axis represent the residue number index, and color (Z-axis) represents the distance of α C atom between X residual index and Y residual index.
obtained in E3-R5, Q15-E22, N27-A30 except G29, and M35-A42. Surprisingly, in contact map analysis, only sheet_(εδδ) shows regular backbone interaction between K16-E22 and G33-I41, as well as between F19-E22 and N27−I31. Such a phenomenon confirmed that (εδδ) isomer may play a critical role on the structural features of Aβ(1−42) monomer, although it prefers nondominating conformation state.
frames from ensemble of (εεε), (εδε), (εδδ), and (δδε). As a result, 5020, 7475, 14474, and 5119 frames (total: 20 000, 20 000, 30 000, and 20 000 frames, respectively) were collected for further analysis. On the basis of above preprocessing (denoted to sheet_isomer), secondary structures of sheet_(εεε), sheet_(εδε), sheet_(εδδ), and sheet_(δδε) are shown in Figure 4. Sheet_(εεε) delivered high content of antiparallel sheet in L17-A21, A30-V36, and V39−I41, which is in good agreement with intrinsic sheet structure in reported Aβ(1−42) freatures. Similarly, in (δδε), antiparallel structure was obtain in L17-A21, G33-V36, and V39−I41. However, different to (εεε) and (δδε), (εδε) showed antiparallel sheet structure not only in V18-D23, K28−I41, but also in E3-H6, such similar N-terminal sheet features have been reported in many literatures stuies.25,50 Additionally, in sheet_(εδδ), antiparallel structure can be
■
CONCLUSION Replica-exchange molecular dynamics simulations were employed to reveal the structural properties of Aβ(1−42) monomer. Our results show that, similar to Aβ(1−40) monomer, significantly different conformational properties were obtained in different isomers of Aβ(1−42). The averaged sheet content of each Aβ(1−42) isomer are slightly higher than that of D
DOI: 10.1021/acschemneuro.6b00375 ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
Research Article
ACS Chemical Neuroscience Author Contributions
Aβ(1−40) isomer except (δδδ) isomer. On the basis of secondary structure analysis and cluster analysis, only (δδδ) of Aβ(1−42) prefers helix-dominating properties. Cluster analysis indicated that (εεε), (εδε), (εδδ), and (δδε) isomers still showed higher sheet tendency in compared with other isomers, although such isomers are located at variously conformational characteristics. Particularly, (εδδ) isomer of Aβ(1−42) monomer has the highest sheet content, where antiparallel β-sheet can be found in K16-E22 (22.0−43.9%), N27-A30 expect G29 (21.9−40.2%), and M35-I41 except G37 (24.1− 43.4%). Further hydrogen bond populations, selected secondary structure and contact map analysis also confirmed that (εδδ) isomer may play a critical role on structural behaviors of Aβ(1−42) monomer. Current study is helpful in understanding structural and potential aggregation features of Aβ(1−42) monomer, and to pinpoint the different characteristics of tautomeric effect between Aβ(1−40) monomer and Aβ(1−42) monomer. In physiology conditions, although it is a mixed state of tautomers in Aβ, one can only focus on sheet-rich and/or sheet-regular structures, and find some ways to inhibit them to overcome AD.
■
METHODS
■
ASSOCIATED CONTENT
H.S. did simulations and wrote the manuscript. J.Y.L. suggested the idea with guidance and wrote the manuscipt. Funding
This work was supported by the National Research Foundation (NRF) grants funded by the Ministry of Education, Science and Technology, subjected to the project EDISON (Educationresearch Integration through Simulation on the Net, Grant No.: 2012M3C1A6035359), and the KISTI supercomputing center through the strategic support program for the supercomputing application research [No. KSC-2014-C2-056]. Notes
The authors declare no competing financial interest.
■
ABBREVIATIONS AD, Alzheimer’s disease; Aβ, amyloid β-peptide; REMD, replica-exchange molecular dynamics; RMSD, root-meansquare deviation
■
(1) Goedert, M., and Spillantini, M. G. (2006) A century of Alzheimer’s disease. Science 314, 777−781. (2) Selkoe, D. J. (2003) Folding proteins in fatal ways. Nature 426, 900−904. (3) Masters, C. L., Simms, G., Weinman, N. A., Multhaup, G., McDonald, B. L., and Beyreuther, K. (1985) Amyloid plaque core protein in Alzheimer disease and down syndrome. Proc. Natl. Acad. Sci. U. S. A. 82, 4245−4249. (4) Kang, J., Lemaire, H. G., Unterbeck, A., Salbaum, J. M., Masters, C. L., Grzeschik, K. H., Multhaup, G., Beyreuther, K., and Muller-Hill, B. (1987) The precursor of Alzheimer’s disease amyloid A4 protein resembles a cell-surface receptor. Nature 325, 733−736. (5) Duff, K., Eckman, C., Zehr, C., Yu, X., Prada, C.-M., Perez-tur, J., Hutton, M., Buee, L., Harigaya, Y., Yager, D., et al. (1996) Increased amyloid-[beta]42(43) in brains of mice expressing mutant presenilin 1. Nature 383, 710−713. (6) Citron, M., Westaway, D., Xia, W., Carlson, G., Diehl, T., Levesque, G., Johnson-wood, K., Lee, M., Seubert, P., Davis, A., et al. (1997) Mutant presenilins of Alzheimer’s disease increase production of 42-residue amyloid [beta]-protein in both transfected cells and transgenic mice. Nat. Med. 3, 67−72. (7) Tomita, T., Maruyama, K., Saido, T. C., Kume, H., Shinozaki, K., Tokuhiro, S., Capell, A., Walter, J., Grünberg, J., Haass, C., et al. (1997) The presenilin 2 mutation (N141I) linked to familial Alzheimer disease (Volga German families) increases the secretion of amyloid β protein ending at the 42nd (or 43rd) residue. Proc. Natl. Acad. Sci. U. S. A. 94, 2025−2030. (8) O’Brien, R. J., and Wong, P. C. (2011) Amyloid Precursor Protein Processing and Alzheimer’s Disease. Annu. Rev. Neurosci. 34, 185−204. (9) Nalivaeva, N. N., and Turner, A. J. (2013) The amyloid precursor protein: A biochemical enigma in brain development, function and disease. FEBS Lett. 587, 2046−2054. (10) Kepp, K. P. (2016) Alzheimer’s disease due to loss of function: A new synthesis of the available data. Prog. Neurobiol. 143, 36−60. (11) Wolfe, M. S., Citron, M., Diehl, T. S., Xia, W., Donkor, I. O., and Selkoe, D. J. (1998) A Substrate-Based Difluoro Ketone Selectively Inhibits Alzheimer’s γ-Secretase Activity. J. Med. Chem. 41, 6−9. (12) Haass, C., and Selkoe, D. J. (2007) Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer’s amyloid betapeptide. Nat. Rev. Mol. Cell Biol. 8, 101−112. (13) Bitan, G., Kirkitadze, M. D., Lomakin, A., Vollers, S. S., Benedek, G. B., and Teplow, D. B. (2003) Amyloid β-protein (Aβ) assembly: Aβ40 and Aβ42 oligomerize through distinct pathways. Proc. Natl. Acad. Sci. U. S. A. 100, 330−335.
Simulation Methods. Crystal structure of the full-length Aβ(1−42) (PDB entry 1IYT51), taken from the Protein Data Bank (http://www.rcsb.org/), was used in current study. Similar to Aβ(1−40) monomer, Aβ(1−42) monomer has three histidine residues located at positions 6, 13, and 14 of the amino acid sequence. So there are eight isomers in Aβ(1−42) monomer because histidine has tautomeric isomers (ε and δ). For example, ε, ε, and δ isomers located at position 6, 13, and 14 in amino acid sequence, respectively, is denoted as (εεδ). Likewise, other isomers are denoted as (εεε), (εδε), (εδδ), (δεε), (δεδ), (δδε), and (δδδ) according to tautomeric forms. The eight tautomeric isomers were prepared by residual substitution with Nε-H or Nδ-H tautomer at positions 6, 13, and 14 of amino acid sequence. The ff99SB nonpolarization force field52 and implicit solvent generalized Born model were employed to perform REMD simulations in Amber14 package.53 SHAKE algorithm was applied to constrain bonds including hydrogen. Particle mesh Ewald summation method was used to describe long-range electrostatics. The value of cutoff distance is infinite for nonbonded interactions. Temperature was controlled by the Langevin thermostat with coupling constant of 1.0 ps. The time step was 2.0 fs. Each simulation has 10 replicas with temperature range from 310 to 510 K. Exchanges between replicas were attempted every 4 ps.
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acschemneuro.6b00375. Convergence details, basic information on simulations, secondary structure distributions in each isomer, conformational states and their probability distributions of (εεε), (εδε), (εδδ), and (δδε) isomers, Hydrogen bond interactions of histidine residues in (εεε), (εδε), (εδδ), and (δδε) isomers (PDF)
■
REFERENCES
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Tel: +82-031-299-4560. ORCID
Hu Shi: 0000-0002-5466-5783 Jin Yong Lee: 0000-0003-0360-5059 E
DOI: 10.1021/acschemneuro.6b00375 ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
Research Article
ACS Chemical Neuroscience (14) Bernstein, S. L., Dupuis, N. F., Lazo, N. D., Wyttenbach, T., Condron, M. M., Bitan, G., Teplow, D. B., Shea, J. E., Ruotolo, B. T., Robinson, C. V., et al. (2009) Amyloid-beta protein oligomerization and the importance of tetramers and dodecamers in the aetiology of Alzheimer’s disease. Nat. Chem. 1, 326−331. (15) Tycko, R. (2003) Insights into the Amyloid Folding Problem from Solid-State NMR. Biochemistry 42, 3151−3159. (16) Luhrs, T., Ritter, C., Adrian, M., Riek-Loher, D., Bohrmann, B., Dobeli, H., Schubert, D., and Riek, R. (2005) 3D structure of Alzheimer’s amyloid-beta(1−42) fibrils. Proc. Natl. Acad. Sci. U. S. A. 102, 17342−17347. (17) Schmidt, M., Sachse, C., Richter, W., Xu, C., Fändrich, M., and Grigorieff, N. (2009) Comparison of Alzheimer Aβ(1−40) and Aβ(1− 42) amyloid fibrils reveals similar protofilament structures. Proc. Natl. Acad. Sci. U. S. A. 106, 19813−19818. (18) Bertini, I., Gonnelli, L., Luchinat, C., Mao, J., and Nesi, A. (2011) A New Structural Model of Aβ40 Fibrils. J. Am. Chem. Soc. 133, 16013−16022. (19) Hoyer, W., Grönwall, C., Jonsson, A., Ståhl, S., and Härd, T. (2008) Stabilization of a β-hairpin in monomeric Alzheimer’s amyloidβ peptide inhibits amyloid formation. Proc. Natl. Acad. Sci. U. S. A. 105, 5099−5104. (20) Rosenman, D. J., Connors, C. R., Chen, W., Wang, C., and García, A. E. (2013) Aβ monomers transiently sample oligomer and fibril-like configurations: ensemble characterization using a combined MD/NMR approach. J. Mol. Biol. 425, 3338−3359. (21) Hou, L., Shao, H., Zhang, Y., Li, H., Menon, N. K., Neuhaus, E. B., Brewer, J. M., Byeon, I.-J. L., Ray, D. G., Vitek, M. P., et al. (2004) Solution NMR Studies of the Aβ(1−40) and Aβ(1−42) Peptides Establish that the Met35 Oxidation State Affects the Mechanism of Amyloid Formation. J. Am. Chem. Soc. 126, 1992−2005. (22) Ahmed, M., Davis, J., Aucoin, D., Sato, T., Ahuja, S., Aimoto, S., Elliott, J. I., Van Nostrand, W. E., and Smith, S. O. (2010) Structural conversion of neurotoxic amyloid-[beta]1−42 oligomers to fibrils. Nat. Struct. Mol. Biol. 17, 561−567. (23) Sgourakis, N. G., Yan, Y., McCallum, S., Wang, C., and Garcia, A. E. (2007) The Alzheimer’s peptides Aβ40 and 42 adopt distinct conformations in water: A combined MD/NMR study. J. Mol. Biol. 368, 1448−1457. (24) Sgourakis, N. G., Merced-Serrano, M., Boutsidis, C., Drineas, P., Du, Z., Wang, C., and Garcia, A. E. (2011) Atomic-level characterization of the ensemble of the Aβ(1−42) monomer in water using unbiased molecular dynamics simulations and spectral algorithms. J. Mol. Biol. 405, 570−583. (25) Lin, Y.-S., Bowman, G. R., Beauchamp, K. A., and Pande, V. S. (2012) Investigating how peptide length and a pathogenic mutation modify the structural ensemble of amyloid beta monomer. Biophys. J. 102, 315−324. (26) Lin, Y.-S., and Pande, V. S. (2012) Effects of Familial Mutations on the Monomer Structure of Aβ(42). Biophys. J. 103, L47−L49. (27) Bateman, R. J., Munsell, L. Y., Morris, J. C., Swarm, R., Yarasheski, K. E., and Holtzman, D. M. (2006) Quantifying CNS protein production and clearance rates in humans using in vivo stable isotope labeling, immunoprecipitation, and tandem mass spectrometry. Nat. Med. 12, 856−861. (28) Mawuenyega, K. G., Sigurdson, W., Ovod, V., Munsell, L., Kasten, T., Morris, J. C., Yarasheski, K. E., and Bateman, R. J. (2010) Decreased clearance of CNS β-amyloid in Alzheimer’s disease. Science 330, 1774. (29) Burdick, D., Soreghan, B., Kwon, M., Kosmoski, J., Knauer, M., Henschen, A., Yates, J., Cotman, C., and Glabe, C. (1992) Assembly and aggregation properties of synthetic Alzheimer’s A4/beta amyloid peptide analogs. J. Biol. Chem. 267, 546−554. (30) Zhang, C. E., Wei, W., Liu, Y. H., Peng, J. H., Tian, Q., Liu, G. P., Zhang, Y., and Wang, J. Z. (2009) Hyperhomocysteinemia increases beta-amyloid by enhancing expression of gamma-secretase and phosphorylation of amyloid precursor protein in rat brain. Am. J. Pathol. 174, 1481−1491.
(31) Shi, H., Kang, B., and Lee, J. Y. (2014) Zn2+ effect on structure and residual hydrophobicity of amyloid β-peptide monomers. J. Phys. Chem. B 118, 10355−10361. (32) Zhang, R., Ai, H., Zhu, X., and Li, Q. (2016) Molecular simulations of human and mouse Aβ1−16 at different pH values: structural characteristics toward understanding Cu2+-coordinated amyloid beta spheres. ChemPhysChem 17, 1656−1668. (33) Beck, M. W., Derrick, J. S., Kerr, R. A., Oh, S. B., Cho, W. J., Lee, S. J. C., Ji, Y., Han, J., Tehrani, Z. A., Suh, N., et al. (2016) Structuremechanism-based engineering of chemical regulators targeting distinct pathological factors in Alzheimer’s disease. Nat. Commun. 7, 13115. (34) Yates, C. M., Butterworth, J., Tennant, M. C., and Gordon, A. (1990) Enzyme activities in relation to pH and lactate in postmortem brain in Alzheimer-type and other dementias. J. Neurochem. 55, 1624− 1630. (35) Barrow, C. J., and Zagorski, M. G. (1991) Solution structures of beta peptide and its constituent fragments: relation to amyloid deposition. Science 253, 179−182. (36) Snyder, S. W., Ladror, U. S., Wade, W. S., Wang, G. T., Barrett, L. W., Matayoshi, E. D., Huffaker, H. J., Krafft, G. A., and Holzman, T. F. (1994) Amyloid-beta aggregation: selective inhibition of aggregation in mixtures of amyloid with different chain lengths. Biophys. J. 67, 1216−1228. (37) Fezoui, Y., Hartley, D. M., Harper, J. D., Khurana, R., Walsh, D. M., Condron, M. M., Selkoe, D. J., Lansbury, P. T., Fink, A. L., and Teplow, D. B. (2000) An improved method of preparing the amyloid beta-protein for fibrillogenesis and neurotoxicity experiments. Amyloid 7, 166−178. (38) Khandogin, J., and Brooks, C. L. (2007) Linking folding with aggregation in Alzheimer’s β-amyloid peptides. Proc. Natl. Acad. Sci. U. S. A. 104, 16880−16885. (39) Ma, K., Clancy, E. L., Zhang, Y., Ray, D. G., Wollenberg, K., and Zagorski, M. G. (1999) Residue-specific pKa measurements of the β-peptide and mechanism of pH-induced amyloid formation. J. Am. Chem. Soc. 121, 8698−8706. (40) Henry, B., Tekely, P., and Delpuech, J. J. (2002) pH and pK determinations by high-resolution solid-state 13C NMR: acid-base and tautomeric equilibria of lyophilized L-histidine. J. Am. Chem. Soc. 124, 2025−2034. (41) Ivanov, I., and Klein, M. L. (2002) Deprotonation of a histidine residue in aqueous solution using constrained ab initio molecular dynamics. J. Am. Chem. Soc. 124, 13380−13381. (42) Huang, Z., Lin, Z., and Song, C. (2007) Protonation processes and electronic spectra of histidine and related ions. J. Phys. Chem. A 111, 4340−4352. (43) Opare, S. K. A., Petoyan, A., Mehrazma, B., and Rauk, A. (2016) Molecular dynamics study of the monomers and dimers of NAcAβ(13−23)NH2: on the effect of pH on the aggregation of the amyloid beta peptide of Alzheimer’s disease. Can. J. Chem. 94, 273− 281. (44) Shi, H., Kang, B., and Lee, J. Y. (2016) Tautomeric Effect of Histidine on the Monomeric Structure of Amyloid β-Peptide(1−40). J. Phys. Chem. B 120, 11405−11411. (45) Humphrey, W., Dalke, A., and Schulten, K. (1996) VMD: visual molecular dynamics. J. Mol. Graphics 14, 33−38. (46) Vigo-Pelfrey, C., Lee, D., Keim, P., Lieberburg, I., and Schenk, D. B. (1993) Characterization of beta-amyloid peptide from human cerebrospinal fluid. J. Neurochem. 61, 1965−1968. (47) Hardy, J. (1997) Amyloid, the presenilins and Alzheimer’s disease. Trends Neurosci. 20, 154−159. (48) Hardy, J., and Selkoe, D. J. (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297, 353−356. (49) Serpell, L. C. (2000) Alzheimer’s amyloid fibrils: structure and assembly. Biochim. Biophys. Acta, Mol. Basis Dis. 1502, 16−30. (50) Ball, K. A., Phillips, A. H., Nerenberg, P. S., Fawzi, N. L., Wemmer, D. E., and Head-Gordon, T. (2011) Homogeneous and heterogeneous tertiary structure ensembles of amyloid-β peptides. Biochemistry 50, 7612−7628. F
DOI: 10.1021/acschemneuro.6b00375 ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
Research Article
ACS Chemical Neuroscience (51) Crescenzi, O., Tomaselli, S., Guerrini, R., Salvadori, S., D’Ursi, A. M., Temussi, P. A., and Picone, D. (2002) Solution structure of the Alzheimer amyloid β-peptide (1−42) in an apolar microenvironment. Eur. J. Biochem. 269, 5642−5648. (52) Salomon-Ferrer, R., Götz, A. W., Poole, D., Le Grand, S., and Walker, R. C. (2013) Routine microsecond molecular dynamics simulations with AMBER on GPUs. 2. explicit solvent particle mesh Ewald. J. Chem. Theory Comput. 9, 3878−3888. (53) Case, D. A., Babin, V., Berryman, J. T., Betz, R. M., Cai, Q., Cerutti, D. S., Cheatham, T. E., III, Darden, T. A., Duke, R. E., and Gohlke, H. et al. (2014) AMBER14, University of California, San Francisco.
G
DOI: 10.1021/acschemneuro.6b00375 ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
