Zn2+ Effect on Structure and Residual Hydrophobicity of Amyloid β

Article pubs.acs.org/JPCB

Zn2+ Effect on Structure and Residual Hydrophobicity of Amyloid β‑Peptide Monomers Hu Shi, Baotao Kang, and Jin Yong Lee* Department of Chemistry, Sungkyunkwan University, 2066 Seobu-Ro, Jangan-Gu, Suwon 440-746, South Korea S Supporting Information *

ABSTRACT: The aggregation of amyloid β-peptide (Aβ peptide) has been associated with the pathogenesis of Alzheimer’s disease (AD). In the present study, we aimed to disclose how Zn2+ affects the Aβ aggregation in detail. Thus, molecular dynamics simulation was implemented to elucidate the changes of structure and residual hydrophobicity upon Zn2+ coordination. Our results show that Zn2+ can strongly influence the structural properties of Aβ40 and Aβ42 by reducing helical formation and increasing turn formation to expose the hydrophobic regions. Furthermore, hydrophobicity of Zn2+-Aβ40 and Zn2+-Aβ42 was much higher than that of each monomer, since Zn2+ binding can significantly influence the hydrophilic domains of Aβ. The further analyses indicate that not only four residues (H6, E11, H13, and H14) but also R5, D7, K16, K28, and terminal residues influence hydrophobicity upon Zn2+ coordination. Importantly, R5, K16, and K28 play a crucial role to regulate solvation-free energies. This work is helpful to understand the fundamental role of Zn2+ in aggregation, which could be useful for further development of new drugs to inhibit Zn2+-Aβ aggregation.

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INTRODUCTION More than 35 million people suffer from Alzheimer’s disease (AD), which is the most common form of dementia.1 One of the histopathological properties of AD is extracellular deposits of fibrillar peptides (called senile plaques).2 And the major component of those plaques are β-amyloid peptides (Aβ) with 39−43 residue fragments, which are generated from the proteolyzed amyloid precursor protein (APP) by β- and γsecretase,3,4 mainly generating amyloidogenic peptides 40 residue fragment (Aβ40, ∼90%) and 42 residue fragment (Aβ42, ∼10%).5−7 Despite the content of the Aβ42 fragment being lower than that of Aβ40, Aβ42 containing I41 and A42 residues has a dramatically increasing propensity to form amyloid fibrils and serious toxicity to neurons.8−10 In structural properties (as shown in Scheme 1), Aβ40 and Aβ42 are

In accordance with the amyloid cascade hypothesis, pristine amyloids are the main neurotoxic substances, and the balance between Aβ production and clearance is crucial in amyloid aggregation.7,16 The APP mutation, β-/γ-secretase’s activity, and metal ion binding can destroy this frail balance and induce aggregation.17 Recently, Zn2+ was known to rapidly induce the Aβ peptides oligomerization under physiological conditions,18,19 indicating that Zn2+ plays an important role in promoting aggregation.7,20,21 Even though there are several Zn2+-coordinated models,22−24 it is widely accepted that Zn2+ is located at H6, E11, H13, and H14 in the N-terminal region by experimental as well as theoretical studies.24−28 The structure of Zn2+ binding to Aβ16 containing all the H6, E11, H13, and H14 residues was determined by nuclear magnetic resonance spectrum in vitro aging [Protein Data Bank (PDB) ID: 1ZE9].28 For the full length Aβ peptides, there reported only structural information by theoretical studies. Wang et al. reported Zn2+ can affect the conformational distribution of Aβ40 by molecular dynamics (MD) simulation. It was found that β-strand/turn formation increased at L17-A21/D23-K28 residues, which may be essential for aggregation.29 Furthermore, Coskuner et al. investigated structural and thermodynamic properties of Zn2+ binding to Aβ40 (Zn2+-Aβ40) and Zn2+ binding to Aβ42 (Zn2+-Aβ42) and found that Zn2+-Aβ42 is more favorable than Zn2+-Aβ40 in thermodynamics.30

Scheme 1. Aβ40/42 Sequencea

a

Amino acids are colored according to Zn2+ binding sites (green) and hydrophobic domains (red).

comprised of hydrophilic N-terminal (D1-K16, metal ions can coordinate to this domain), central hydrophobic core (L17A21, CHC), hydrophilic patch (E22-G29), and C-terminal hydrophobic domain (A30-V40/A42, HP2).11,12 CHC and HP2 are considered to be essential for Aβ aggregation, especially CHC because it is regarded as the critical region for the initiation of aggregation and fibril formation.13−15 © XXXX American Chemical Society

Received: May 15, 2014 Revised: August 9, 2014

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Reported in these articles are structural properties of Zn2+coordinated Aβ (Zn2+-Aβ). However, the details of hydrophobic properties in the presence of Zn2+ are still unclear, which is strongly correlated with the aggregation behavior. Thus, to investigate the hydrophobic properties of each residue of the entire proteins (Aβ40 and Aβ42) under the influence of Zn2+ coordination will be helpful for understanding of the aggregation behavior, hence for treating AD. In this work, we investigated four models (Aβ40, Zn2+-Aβ40, Aβ42, Zn2+-Aβ42) in order to get insight into the molecular mechanisms and detect the hydrophobic properties by MD simulations. In metalloprotein studies, there are three approaches in simulations: (1) bonded model, (2) nonbonded model, and (3) the cationic dummy atom model.31 In order to accurately describe the Zn2+-coordinated Aβ, it is beneficial to use the bonded model which defines bonds, angles, and dihedral angles between the metal ions and coordinated atoms. We assume H6, E11, H13, and H14 binding sites, as shown in Figure 1. In this

Temperature (310 K) and pressure (1 atm) were controlled by the Berendsen thermostat and barostat with coupling constants of 1.0 and 2.0 ps, respectively. Single trajectory (100 ns for each trajectory with a time step of 2.0 fs) for each simulation was collected in our study. The molecular mechanics generalized-Born surface area (MM/GBSA) method was used to get solvation free-energy estimation. The solvation free energy of the Zn2+-Aβ conformations were obtained using the conformational ensemble after removing Zn2+. Solvation free energy (Gsolv) was obtained by the sum of polar solvation free energy (GGB), which was estimated by the generalized Born model and the nonpolar component of the solvation free energy (GSA), which was computed from the solvent accessible surface area.

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RESULTS AND DISCUSSION Distances between Zn2+ and the coordinating atoms are available in Figure S1 of the Supporting Information. The distances between Zn2+ and N atoms of H6, H13, and H14 are around 2.08 Å, while the distance between the Zn2+ and O atoms of E11 is about 2.28 Å. These stable values during the simulation indicate that MTK++/MCPB can provide a desirable condition for this study. Additionally, root-meansquare deviation (RMSD) curves (Figure S2 of the Supporting Information) show that RMSD in all cases (Aβ40, Zn2+-Aβ40, Aβ42, and Zn2+-Aβ42) converge very well. Therefore, only the last 40 ns converged trajectories were used to analyze the data in this study. In the present paper, all histidines with and without zinc binding adopted the deprotonated state as shown in Table S1 of the Supporting Information. Previous literature40 mentioned that both Aβ40 and Aβ42 have a total charge of −3, and all the three histidines were found to be deprotonated in Zn2+coordinated Aβ protein as confirmed from the Zn2+···N distances by NMR studies. Therefore, we used the deprotonated states for all three histidines in the present study. Until now, the protonation state of histidines was experimentally confirmed for Zn2+-coordinated Aβ but not for Aβ. However, some literature argued that at the physiological condition, coordination of zinc ion to each histidine can release ∼0.3 proton for Zn-finger peptides.41,42 Thus, we tested to detect the structural properties of Aβ40 with protonated H13 residue. We chose the central histidine of the three histidines because Li et al. mentioned 0.3 proton release.42 We extended 50 ns simulation with protonated H13 residue, and the last 40 ns (converged) trajectory was used to analyze the data. We found the backbone RMSD of most populated cluster structures between the previous deprotonated, and this protonated state was more than 0.9 Å. Therefore, we identified that the protonation state can give a crucial contribution for the conformation changes, hence the hydrophobicity. However, as mentioned above, our present study adopted the histidines all deprotonated as the previous study for Aβ. As shown in Figure 2, the free-energy landscapes display the conformational preferences of Aβ40, Zn2+-Aβ40, Aβ42, and Zn2+-Aβ42 in aqueous solution based on their radius of gyration (Rg) and RMSD values. The preferred structures were generated in specific basins with the lowest energy state (red in Figure 2). All of the structures in each basin were shown in Figure S3 of the Supporting Information. As seen in Figure 2, there is one basin with a wide range of RMSD in Aβ40 (Figure 2A) and three basins in Aβ42 (Figure 2C), indicating that Aβ40 and Aβ42 are random peptides. This is in agreement with

Figure 1. Initial structure of Zn2+-Aβ42 in simulation. H6, E11, H13, and H14 are shown in cyan, Zn2+ in gray, and the N-terminal as the blue sphere.

report, we try to understand the reason why and how the hydrophobicity of Aβ increases upon Zn2+ coordination. To this end, we investigated the structural changes and compared the residual hydrophobicity under the influence of Zn2+ coordination.

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SIMULATION DETAILS The parameters of the active site (Zn2+ binding site), which are available in Table S1−S3 of the Supporting Information, were obtained by density functional theory (DFT) calculations employing M06 exchange functional with 6-31+G* basis sets,32 using a suite of Gaussian 0933 referring to the experimental structures (PDB ID: 1ZE9). Then the parameters were transformed into a corresponding force field by MTK+ +/MCPB module31 in AmberTools13. For starting structures, the secondary structure formation of D1-K16 fragment was taken from PDB ID: 1ZE9 and the L17-V40/A42 fragment from PDB ID: 1IYT.34 The structural changes were analyzed using visual molecular dynamics (VMD).35 In MD simulations, Amber1236 with ff99SB force field37 was employed. The TIP3P model was used to describe solvent water.38 The SHAKE algorithm was applied to constrain bonds, including hydrogen.39 The particle mesh Ewald summation method was employed to describe long-range electrostatics. The value of cutoff distance for nonbonded interactions is 12 Å. B

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Figure 2. Free-energy landscape of (A) Aβ40, (B) Zn2+-Aβ40, (C) Aβ42, and (D) Zn2+-Aβ42. The color scale is given in kilocalories per mol.

Figure 3. Secondary structure components per residue of four simulations: (A) Aβ40, (B) Zn2+-Aβ40, (C) Aβ42, and (D) Zn2+-Aβ42. The color scale is the percentage of structure component.

previous results.11,12,43,44 After Zn2+ coordination, it is clear that only one basin occurs in Zn2+-Aβ40 (Figure 2B) and Zn2+Aβ42 (Figure 2D). The basin of Zn2+-Aβ40 (Zn2+-Aβ42) is located at Rg value of 9.88−9.95 Å (9.90−10.10 Å) and RMSD value of 1.45−1.55 Å (1.78−2.22 Å). Thus, we can realize that

Zn2+ can significantly influence the structural properties, indicating that Zn2+-Aβ40 and Zn2+-Aβ42 structures could be stabilized by Zn2+ coordination to the N-terminal, which is consistent with our previous study.30 C

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formation and increasing turn formation, which is in accordance with the previous study.29 Hydrophobic interactions have been considered to play an important role in Aβ oligomers and aggregation processes.7,45,46 The solvation free energy has been commonly utilized as an important criterion to assess the hydrophobicity of peptides. The calculated average solvation free energies (Gsolv) are listed in Table 1 along with its component of polar solvation free energy (GGB) and nonpolar component of the solvation free energy (GSA). These solvation free energies were evaluated through the MM/GBSA method, which has been demonstrated to give satisfactory performance and efficiency.47 The solvation free energy of Aβ40/Aβ42 increased from −689.3/−667.9 to −534.7/−641.6 kcal/mol upon Zn2+ coordination. These results indicate that Zn2+ can enhance the hydrophobicity, hence the aggregation, of Aβ monomers. Additionally, the solvation free energy of Zn2+-Aβ40 is much larger than that of Zn2+-Aβ42 in aqueous solution, indicating Zn2+-Aβ40 is much easier to aggregate. To fully assess the role of each residue on the hydrophobicity, we investigated the residual solvation free energies, and the results are shown in Figure 4. It is obvious to observe that there is a slight fluctuation after Zn2+ coordination to Aβ40 and Aβ42 in CHC and HP2 domains except for hydrophilic end residues, which indicates that Zn2+ binding cannot give a significant influence on the solvation free energy in the hydrophobic domains of Aβ. In other words, most of the changes of solvation free energy due to Zn2+ coordination arises from the hydrophilic N-terminal and E22-G29 residues. Not surprisingly, the solvation free energies of H6, E11, H13, and H14 residues are also affected by Zn2+ coordination. These four residues contribute 104.0 and 64.7 kcal/mol by Zn 2+ coordination to Aβ40 and Aβ42, respectively. In particular, E11 residue contributes 69.9 and 56.1% to the total solvation free energy of Zn2+-Aβ40 and Zn2+-Aβ42, respectively, suggesting E11 plays a crucial role.

Table 1. Average Solvation Free Energies

GGB GSA Gsolv

Aβ40 (kcal/mol)

Zn2+-Aβ40 (kcal/mol)

Aβ42 (kcal/mol)

Zn2+-Aβ42 (kcal/mol)

−716.8 27.5 −689.3

−559.2 24.4 −534.7

−693.6 25.6 −667.9

−668.4 26.8 −641.6

The secondary structure components per residue were calculated and displayed in Figure 3 to detect the structural properties of Aβ40, Zn2+-Aβ40, Aβ42, and Zn2+-Aβ42. It is clear for Aβ40 that the helical formation occurred with high probability at H6-S8 (58%) residues in the N-terminal and I32L34 (72−73%) residues in HP2 (Figure 3A). However, after Zn2+ coordination to Aβ40 (Figure 3B), helical formation at I32-L34 residues significantly decreased. In particular, helical forms at L34-G37 residues transformed into turn formation (33−77%). Because of the Zn2+ coordination to the N-terminal, E3-D7 (63−95%) and V12-H14 (54−56%) residues changed their geometries into helical forms. F20-G25 except for D23 adopted turn formation. For Aβ42 (as shown in Figure 3C), the helical formation was found at K16-F19 (46−89%) and K28V36 (40−100%) residues. However, after Zn2+ coordination to Aβ42 (Figure 3D), the helical formation at K16-F19, K28-I31, and M35-V36 residues disappeared, while helical forms are newly generated at V12-H14 residues. Moreover, D23-S26 residues adopted turn formation (33−78%). For the L17-V40/ A42 fragment, Zn2+-Aβ40 has more turn (22%) and sheet (1%), while less coil (18%) and helical (5%) formation than Aβ40. Meanwhile, Zn2+-Aβ42 has more turn (2%), sheet (6%), and coil (17%), while less helical (23%) formation than Aβ42. We can see the structural features due to Zn2 coordination are similar in both Aβ40 and Aβ42. It can be concluded that Zn2+ can directly influence the conformational change of amyloid βpeptide monomers (i.e., V12-H14 residues changed into helical forms). Moreover, the structural changes at L17-V40/A42 residues exposed hydrophobic areas by decreasing the helical

Figure 4. Decomposed solvation free energies of Aβ40, Zn2+-Aβ40, Aβ42, and Zn2+-Aβ42. D

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Figure 5. Contact map of (A) Aβ40 (upper triangle), (B) Zn2+-Aβ40 (lower triangle), (C) Aβ42 (upper triangle), and (D) Zn2+-Aβ42 (lower triangle). The color scale is the distance of alpha C in Å.

between the A30-G37/Y10-A21 and the F20-D23/D23-L34 residues. The increased long-range contacts by Zn2+ coordination can enhance the side-chain interactions in Aβ40 and Aβ42, which are responsible for the stabilization of Zn2+-Aβ40 and Zn2+-Aβ42. It is clearly seen in Figure 6 that, for both Aβ40 and Aβ42, Zn2+ coordination causes more exposure of the K16 residue in aqueous solvation. This result is consistent with previous studies, suggesting that K16 can be predominantly exposed to the solvent,48,49 and this process can be available for interaction with other monomers, cell membranes, or potential inhibitors.50 The solvation free energy of K28 residue of Aβ40 was increased by 31.2 kcal/mol in Zn2+ coordination due to the interaction with D7 residue, while that of Aβ42 was decreased by −27.9 kcal/mol due to the exposure to water solvent (Figure 6). The solvation free energy of the terminal residue V40 of Aβ40 increased by 40.6 kcal/mol upon Zn2+ coordination, while that of D1 of Aβ42 decreased by −29.5 kcal/mol. Our result is related to the previous remark that Aβ40 fibril will lose toxicity via substituting R5, K16, and K28 with alanine in human embryonic kidney cells.51 In consideration that these charged residues are responsible for the toxicity of Aβ52 and they are exposed to water even after Zn2+ coordination, it can be speculated that Zn2+-Aβ not only has stronger hydrophobicity than each monomer to enhance the aggregation but maintains the toxicity to membrane.

Figure 6. Most populated cluster structure of (A) Aβ40, (B) Zn2+Aβ40, (C) Aβ42, and (D) Zn2+-Aβ42.

Moreover, when H6 is involved in Zn2+ coordination, adjacent D7 (negatively charged residue) residue is compelled, and the extent of exposure to the aqueous medium is reduced. This obviously causes an increased hydrophobicity of Aβ40 and Aβ42 upon Zn2+ coordination. Remarkably, as seen in Figure 4, a dramatic change of the solvation free energy was found at residues of R5, K16, and K28. The solvation free energy of the positively charged residue R5 of Aβ40 was significantly reduced (by −34.8 kcal/mol) upon Zn2+ coordination, while it was only slightly reduced (by −1.2 kcal/mol) for Aβ42. On the other hand, the solvation free energy of the positively charged residue K16 for both Aβ40 and Aβ42 was significantly reduced upon Zn2+ coordination by −26.0 and −23.5 kcal/mol, respectively. The contact maps and representative conformations of Aβ40, Zn2+-Aβ40, Aβ42, and Zn2+-Aβ42 are shown in Figures 5 and 6. From Figure 5, it can be seen that, compared with each monomer, Zn2+-Aβ40/Zn2+-Aβ42 has more long-range contacts between the V24-L34/K28-G35 and the F4-H13/D1-G25 residues than Aβ40/Aβ42, where the contacts were formed

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CONCLUSION The structural changes and residual hydrophobicity of Aβ40 and Aβ42 under the influence of Zn2+ were investigated by MD simulations. It was found from the free energy landscape that Zn2+-Aβ40 and Zn2+-Aβ42 were stabilized compared to Aβ40 and Aβ42. Due to the Zn2+ coordination to Aβ40, the helical formation was decreased at I32-L34 residues in HP2 and turn formation appeared at L34-G37 and F20-G25 residues except D23, while Zn2+ coordination to Aβ42 resulted in the decreased helical formation at K16-F19, K28-I31, and M35-V36 residues and the appearance of turn formation at D23-S26 residues. Overall, the decreased helical formation and appearance of turn formation implies that more hydrophobic region can be E

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exposed owing to Zn2+ coordination. The increased long-range contacts by Zn2+ coordination can enhance the side-chain interactions in Aβ40 and Aβ42, which are responsible for the stabilization of Zn2+-Aβ40 and Zn2+-Aβ42. Moreover, Zn2+ significantly influences the solvation free energies of Aβ monomers. Residual solvation free energies showed that great changes only occur in hydrophilic domains. The R5, D7, E11, K16, and K28 residues gave a significant change of the residual hydrophobicity upon Zn2+ coordination. In particular, E11 played a major role in enhancing hydrophobicity on Zn2+ coordination. Considering that these charged residues are exposed to water even after Zn2+ coordination, Zn2+-Aβ is considered to maintain toxicity to membrane similar to Aβ. This result is useful to reveal AD pathogenesis, and to design drugs to overcome Zn2+-Aβ aggregation.

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(9) Hardy, J. Amyloid, the presenilins and Alzheimer’s disease. Trends Neurosci. 1997, 20, 154−159. (10) Vigo-Pelfrey, C.; Lee, D.; Keim, P.; Lieberburg, I.; Schenk, D. B. Characterization of beta-amyloid peptide from human cerebrospinal fluid. J. Neurochem. 1993, 61, 1965−1968. (11) Rauk, A. The chemistry of Alzheimer’s disease. Chem. Soc. Rev. 2009, 38, 2698−2715. (12) DeToma, A. S.; Salamekh, S.; Ramamoorthy, A.; Lim, M. H. Misfolded proteins in Alzheimer’s disease and type II diabetes. Chem. Soc. Rev. 2012, 41, 608−621. (13) Wood, S. J.; Wetzel, R.; Martin, J. D.; Hurle, M. R. Prolines and amyloidogenicity in fragments of the Alzheimer’s peptide beta/A4. Biochemistry 1995, 34, 724−730. (14) Esler, W. P.; Stimson, E. R.; Ghilardi, J. R.; Lu, Y. A.; Felix, A. M.; Vinters, H. V.; Mantyh, P. W.; Lee, J. P.; Maggio, J. E. Point substitution in the central hydrophobic cluster of a human betaamyloid congener disrupts peptide folding and abolishes plaque competence. Biochemistry 1996, 35, 13914−13921. (15) Massi, F.; Peng, J. W.; Lee, J. P.; Straub, J. E. Simulation study of the structure and dynamics of the Alzheimer’s amyloid peptide congener in solution. Biophys. J. 2001, 80, 31−44. (16) Mattson, M. P. Pathways towards and away from Alzheimer’s disease. Nature 2004, 430, 631−639. (17) Zhang, C. E.; Wei, W.; Liu, Y. H.; Peng, J. H.; Tian, Q.; Liu, G. P.; Zhang, Y.; Wang, J. Z. Hyperhomocysteinemia increases betaamyloid by enhancing expression of gamma-secretase and phosphorylation of amyloid precursor protein in rat brain. Am. J. Pathol. 2009, 174, 1481−1491. (18) Bush, A. I.; Pettingell, W. H.; Multhaup, G.; d Paradis, M.; Vonsattel, J. P.; Gusella, J. F.; Beyreuther, K.; Masters, C. L.; Tanzi, R. E. Rapid induction of Alzheimer A beta amyloid formation by zinc. Science 1994, 265, 1464−1467. (19) Lim, K. H.; Kim, Y. K.; Chang, Y. T. Investigations of the molecular mechanism of metal-induced Abeta (1−40) amyloidogenesis. Biochemistry 2007, 46, 13523−13532. (20) Pithadia, A. S.; Lim, M. H. Metal-associated amyloid-beta species in Alzheimer’s disease. Curr. Opin. Chem. Biol. 2012, 16, 67− 73. (21) Faller, P.; Hureau, C. Bioinorganic chemistry of copper and zinc ions coordinated to amyloid-beta peptide. Dalton Trans. 2009, 1080− 1094. (22) Danielsson, J.; Pierattelli, R.; Banci, L.; Graslund, A. Highresolution NMR studies of the zinc-binding site of the Alzheimer’s amyloid beta-peptide. FEBS J. 2007, 274, 46−59. (23) Curtain, C. C.; Ali, F.; Volitakis, I.; Cherny, R. A.; Norton, R. S.; Beyreuther, K.; Barrow, C. J.; Masters, C. L.; Bush, A. I.; Barnham, K. J. Alzheimer’s disease amyloid-beta binds copper and zinc to generate an allosterically ordered membrane-penetrating structure containing superoxide dismutase-like subunits. J. Biol. Chem. 2001, 276, 20466− 20473. (24) Gaggelli, E.; Janicka-Klos, A.; Jankowska, E.; Kozlowski, H.; Migliorini, C.; Molteni, E.; Valensin, D.; Valensin, G.; Wieczerzak, E. NMR studies of the Zn2+ interactions with rat and human betaamyloid (1−28) peptides in water-micelle environment. J. Phys. Chem. B 2008, 112, 100−109. (25) Yang, D. S.; McLaurin, J.; Qin, K.; Westaway, D.; Fraser, P. E. Examining the zinc binding site of the amyloid-beta peptide. Eur. J. Biochem. 2000, 267, 6692−6698. (26) Zirah, S.; Stefanescu, R.; Manea, M.; Tian, X.; Cecal, R.; Kozin, S. A.; Debey, P.; Rebuffat, S.; Przybylski, M. Zinc binding agonist effect on the recognition of the beta-amyloid (4−10) epitope by anti-betaamyloid antibodies. Biochem. Biophys. Res. Commun. 2004, 321, 324− 328. (27) Xu, L.; Wang, X.; Wang, X. Effects of Zn(2+) binding on the structural and dynamic properties of amyloid beta peptide associated with Alzheimer’s disease: Asp(1) or Glu(11)? ACS Chem. Neurosci. 2013, 4, 1458−1468. (28) Zirah, S.; Kozin, S. A.; Mazur, A. K.; Blond, A.; Cheminant, M.; Segalas-Milazzo, I.; Debey, P.; Rebuffat, S. Structural changes of region

ASSOCIATED CONTENT

S Supporting Information *

Optimized force field parameters, distances between Zn2+ and coordinated atoms, backbone root-mean-square deviation, and basin structures in the free-energy landscape. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Tel: (82) 31-299-4560. Fax: (82) 31-290-7075. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by National Research Foundation (NRF) (Grants 2007-0056343 and 2012K1A2B1A03000362) funded by the Korean government (MEST). We also acknowledge the financial support from the Ministry of Education, Science and Technology, subjected to the project EDISON (Education-research Integration through Simulation on the Net, Grant 2012M3C1A6035359).

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REFERENCES

(1) Goedert, M.; Spillantini, M. G. A century of Alzheimer’s disease. Science 2006, 314, 777−781. (2) Selkoe, D. J. Folding proteins in fatal ways. Nature 2003, 426, 900−904. (3) Masters, C. L.; Simms, G.; Weinman, N. A.; Multhaup, G.; McDonald, B. L.; Beyreuther, K. Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc. Natl. Acad. Sci. U.S.A. 1985, 82, 4245−4249. (4) Kang, J.; Lemaire, H. G.; Unterbeck, A.; Salbaum, J. M.; Masters, C. L.; Grzeschik, K. H.; Multhaup, G.; Beyreuther, K.; Muller-Hill, B. The precursor of Alzheimer’s disease amyloid A4 protein resembles a cell-surface receptor. Nature 1987, 325, 733−736. (5) Jakob-Roetne, R.; Jacobsen, H. Alzheimer’s disease: From pathology to therapeutic approaches. Angew. Chem., Int. Ed. 2009, 48, 3030−3059. (6) Hamley, I. W. The amyloid beta peptide: A chemist’s perspective. Role in Alzheimer’s and fibrillization. Chem. Rev. 2012, 112, 5147− 5192. (7) Kepp, K. P. Bioinorganic chemistry of Alzheimer’s disease. Chem. Rev. 2012, 112, 5193−5239. (8) 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. F

dx.doi.org/10.1021/jp504779m | J. Phys. Chem. B XXXX, XXX, XXX−XXX

The Journal of Physical Chemistry B

Article

(48) Zhang, S.; Casey, N.; Lee, J. P. Residual structure in the Alzheimer’s disease peptide: Probing the origin of a central hydrophobic cluster. Folding Des. 1998, 3, 413−422. (49) Zhang, S.; Iwata, K.; Lachenmann, M. J.; Peng, J. W.; Li, S.; Stimson, E. R.; Lu, Y.; Felix, A. M.; Maggio, J. E.; Lee, J. P. The Alzheimer’s peptide a beta adopts a collapsed coil structure in water. J. Struct. Biol. 2000, 130, 130−141. (50) Chen, Z.; Krause, G.; Reif, B. Structure and orientation of peptide inhibitors bound to beta-amyloid fibrils. J. Mol. Biol. 2005, 354, 760−776. (51) Yoshiike, Y.; Akagi, T.; Takashima, A. Surface structure of amyloid-beta fibrils contributes to cytotoxicity. Biochemistry 2007, 46, 9805−9812. (52) Dobson, C. M. Protein aggregation and its consequences for human disease. Protein Pept. Lett. 2006, 13, 219−227.

1−16 of the Alzheimer disease amyloid beta-peptide upon zinc binding and in vitro aging. J. Biol. Chem. 2006, 281, 2151−2161. (29) Li, W.; Zhang, J.; Su, Y.; Wang, J.; Qin, M.; Wang, W. Effects of zinc binding on the conformational distribution of the amyloid-beta peptide based on molecular dynamics simulations. J. Phys. Chem. B 2007, 111, 13814−13821. (30) Wise-Scira, O.; Xu, L.; Perry, G.; Coskuner, O. Structures and free energy landscapes of aqueous zinc(II)-bound amyloid-beta(1−40) and zinc(II)-bound amyloid-beta(1−42) with dynamics. J. Biol. Inorg. Chem. 2012, 17, 927−938. (31) Peters, M. B.; Yang, Y.; Wang, B.; Fusti-Molnar, L.; Weaver, M. N.; Merz, K. M., Jr. Structural Survey of Zinc Containing Proteins and the Development of the Zinc AMBER Force Field (ZAFF). J. Chem. Theory. Comput. 2010, 6, 2935−2947. (32) Zhao, Y.; Truhlar, D. The M06 suite of density functionals for main group thermochemistry, thermochemical kinetics, noncovalent interactions, excited states, and transition elements: Two new functionals and systematic testing of four M06-class functionals and 12 other functionals. Theor. Chem. Acc. 2008, 120, 215−241. (33) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; et al. Gaussian 09; Gaussian, Inc.: Wallingford, CT, 2009. (34) Crescenzi, O.; Tomaselli, S.; Guerrini, R.; Salvadori, S.; D’Ursi, A. M.; Temussi, P. A.; Picone, D. Solution structure of the Alzheimer amyloid beta-peptide (1−42) in an apolar microenvironment. Similarity with a virus fusion domain. Eur. J. Biochem. 2002, 269, 5642−5648. (35) Humphrey, W.; Dalke, A.; Schulten, K. VMD: visual molecular dynamics. J. Mol. Graph. 1996, 14 (33−38), 27−28. (36) Case, D. A.; Darden, T. A.; Cheatham, T. E. I.; Simmerling, C. L.; Wang, J.; Duke, R. E.; Luo, R.; Walker, R. C.; Zhang, W.; Merz, K. M.; et al. AMBER12; University of California: San Francisco, 2012. (37) Salomon-Ferrer, R.; Götz, A. W.; Poole, D.; Le Grand, S.; Walker, R. C. Routine Microsecond Molecular Dynamics Simulations with AMBER on GPUs. 2. Explicit Solvent Particle Mesh Ewald. J. Chem. Theory. Comput. 2013, 9, 3878−3888. (38) Jorgensen, W. L.; Chandrasekhar, J.; Madura, J. D.; Impey, R. W.; Klein, M. L. Comparison of simple potential functions for simulating liquid water. J. Chem. Phys. 1983, 79, 926−935. (39) Miyamoto, S.; Kollman, P. A. Settle: An analytical version of the SHAKE and RATTLE algorithm for rigid water models. J. Comput. Chem. 1992, 13, 952−962. (40) Kepp, K. P. Bioinorganic chemistry of Alzheimer’s disease. Chem. Rev. 2012, 112, 5193−5239. (41) Blasie, C. A.; Berg, J. M. Structure-based thermodynamic analysis of a coupled metal binding-protein folding reaction involving a zinc finger peptide. Biochemistry 2002, 41, 15068−15073. (42) Li, W.; Zhang, J.; Wang, J.; Wang, W. Metal-coupled folding of Cys2His2 zinc-finger. J. Am. Chem. Soc. 2008, 130, 892−900. (43) Wise-Scira, O.; Xu, L.; Kitahara, T.; Perry, G.; Coskuner, O. Amyloid-beta peptide structure in aqueous solution varies with fragment size. J. Chem. Phys. 2011, 135, 205101−205113. (44) Xu, J.; Zhang, J. Z. H.; Xiang, Y. Molecular dynamics simulation and computational two-dimensional infrared spectroscopic study of model amyloid β-peptide oligomers. J. Phys. Chem. A 2013, 117, 6373−6379. (45) Savelieff, M. G.; Lee, S.; Liu, Y.; Lim, M. H. Untangling amyloidbeta, tau, and metals in Alzheimer’s disease. ACS Chem. Biol. 2013, 8, 856−865. (46) Lin, E. I.; Shell, M. S. Can peptide folding simulations provide predictive information for aggregation propensity? J. Phys. Chem. B 2010, 114, 11899−11908. (47) Hou, T.; Wang, J.; Li, Y.; Wang, W. Assessing the performance of the MM/PBSA and MM/GBSA methods. 1. The accuracy of binding free energy calculations based on molecular dynamics simulations. J. Chem. Inf. Model. 2011, 51, 69−82. G

dx.doi.org/10.1021/jp504779m | J. Phys. Chem. B XXXX, XXX, XXX−XXX