Comparative Molecular Dynamics Study of Aβ Adsorption on the Self

Nov 23, 2009 - Our simulations have showed that Aβ peptides are very mobile on the hydrophilic surface due to weak surface affinity. Thus, those weak...
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Comparative Molecular Dynamics Study of Aβ Adsorption on the Self-Assembled Monolayers Qiuming Wang,†,§ Chao Zhao,†,§ Jun Zhao,† Jingdai Wang,‡ Jui-Chen Yang,† Xiang Yu,† and Jie Zheng*,† † ‡

Department of Chemical and Biomolecular Engineering University of Akron, Akron, Ohio 44325 and Department of Chemical Engineering, Zhejiang University, Hangzhou 310027, China. § These authors contributed equally to this work. Received August 17, 2009. Revised Manuscript Received October 18, 2009

The adsorption and aggregation of the amyloid-β (Aβ) peptides on the cell membrane plays a causal role in the pathogenesis of Alzheimer’s disease. Here, we report all-atom molecular dynamics (MD) simulations to study the interactions of Aβ oligomer with self-assembled monolayers (SAMs) terminated with hydrophobic CH3 and hydrophilic OH functional groups, with particular interests in how surface chemistry and Aβ orientation affect the adsorption behavior of Aβ. Simulation results show that the CH3-SAM has a stronger binding affinity to Aβ than the OH-SAM does, although both surfaces can induce Aβ adsorption. Regardless of the characteristics of the surface, the hydrophobic C-terminal region is more likely to be adsorbed on the SAMs, indicating a preferential orientation and interface for Aβ adsorption. Structural and energetic comparison among six Aβ-SAM systems further reveals that Aβ orientation, SAM surface hydrophobicity, and interfacial waters all determine Aβ adsorption behavior on the surface, highlighting the importance of hydrophobic interactions at the interface. This work may provide parallel insights into the interactions of Aβ with lipid bilayers.

Introduction Alzheimer’s disease (AD) is pathologically characterized by intracellular neurofibrillary tangles and extracellular amyloid plaques in the human brains.1,2 The primary component of amyloid plaques is an amphiphilic 39-42 residue polypeptide (amyloid-β, Aβ), comprising of hydrophilic N-terminus (residues 1-28) and hydrophobic C-terminus (residues 29-40/42).3 Increasing evidence from genetic, pathological, and cell culture studies4-6 have implicated that soluble Aβ oligomers rather than monomers or mature fibrils are major cytotoxic species responsible for neuron death. These Aβ oligomers adopt multiple distinct structural morphologies but with high cross-β conformation under different environmental conditions,7,8 which may exert different extents of toxicity in cells.5 Intensive studies have mainly focused on the morphology and kinetics of Aβ peptides at different stages of aggregation (i.e., oligomers, protofibrils, and fibrils) in bulk solution and on the surface. Studies of Aβ deposition on the surfaces are more physiologically important because of its relevance to the neurotoxicity of amyloids. Many different surfaces have been used to study the Aβ-surface interactions and their effects on the *To whom correspondence should be addressed. E-mail: [email protected]. (1) Buxbaum, J. D.; Koo, E. H.; Greengard, P. Proc. Natl. Acad. Sci. U.S.A. 1993, 90 (19), 9195-9198. (2) Lin, H.; Bhatia, R.; Lal, R. FASEB J. 2001, 15 (13), 2433-2444. (3) Wertkin, A. M.; Turner, R. S.; Pleasure, S. J.; Golde, T. E.; Younkin, S. G.; Trojanowski, J. Q.; Lee, V. M. Proc. Natl. Acad. Sci. U.S.A. 1993, 90 (20), 9513-9517. (4) Kayed, R.; Head, E.; Thompson, J. L.; McIntire, T. M.; Milton, S. C.; Cotman, C. W.; Glabe, C. G. Science 2003, 300 (5618), 486-489. (5) Bucciantini, M.; Giannoni, E.; Chiti, F.; Baroni, F.; Formigli, L.; Zurdo, J.; Taddei, N.; Ramponi, G.; Dobson, C. M.; Stefani, M. Nature 2002, 416 (6880), 507-511. (6) Cleary, J. P.; Walsh, D. M.; Hofmeister, J. J.; Shankar, G. M.; Kuskowski, M. A.; Selkoe, D. J.; Ashe, K. H. Nat. Neurosci. 2005, 8 (1), 79-84. (7) Petkova, A. T.; Leapman, R. D.; Guo, Z.; Yau, W.-M.; Mattson, M. P.; Tycko, R. Science 2005, 307 (5707), 262-265. (8) Zhu, M.; Han, S.; Zhou, F.; Carter, S. A.; Fink, A. L. J. Biol. Chem. 2004, 279 (23), 24452-24459.

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Aβ aggregation and/or toxicity, including “hard” inorganic substrates,9-13 organic monolayers,14,15 and “soft” biological membranes.16-19 In fact, hydrophobic and electrostatic interactions between Aβ and membrane have been implicated in both toxicity and aggregation of Aβ. But, how these interactions drive Aβ to associate with cells and then induce cytotoxicity in cells still remains unclear, i.e., whether or not Aβ toxicity is caused by the formation of selective ion channel by inserting Aβ monomers/oligomers into the cell membrane20,21 or by the unselective disruption of membrane permeability and integrity by binding Aβ to cell surface.22,23 Additionally, due to the complex nature of cell membranes, the levels of cholesterol and ganglioside in cell membranes,24,25 lipid (9) Jiang, D.; Dinh, K. L.; Ruthenburg, T. C.; Zhang, Y.; Su, L.; Land, D. P.; Zhou, F. J. Phys. Chem. B 2009, 113 (10), 3160-3168. (10) Giacomelli, C. E.; Norde, W. Macromol. Biosci. 2005, 5 (5), 401-407. (11) Kowalewski, T.; Holtzman, D. M. Proc. Natl. Acad. Sci. U.S.A. 1999, 96 (7), 3688-3693. (12) Giacomelli, C. E.; Norde, W. Biomacromolecules 2003, 4 (6), 1719-1726. (13) Arimon, M.; Diez-Perez, I.; Kogan, M. J.; Durany, N.; Giralt, E.; Sanz, F.; Fernandez-Busquets, X. FASEB J. 2005, 04-3137fje. (14) McMasters, M. J.; Hammer, R. P.; McCarley, R. L. Langmuir 2005, 21 (10), 4464-4470. (15) Ryu, J.; Joung, H.-A.; Kim, M.-G.; Park, C. B. Anal. Chem. 2008, 80 (7), 2400-2407. (16) Elena, M.; Andreas, K.; Alfred, B.; Helmuth, M.; Gerald, B. ChemBioChem 2005, 6 (10), 1817-1824. (17) Yip, C. M.; Darabie, A. A.; McLaurin, J. J. Mol. Biol. 2002, 318 (1), 97-107. (18) Kayed, R.; Sokolov, Y.; Edmonds, B.; McIntire, T. M.; Milton, S. C.; Hall, J. E.; Glabe, C. G. J. Biol. Chem. 2004, 279 (45), 46363-46366. (19) Chi, E. Y.; Ege, C.; Winans, A.; Majewski, J.; Wu, G.; Kjaer, K.; Lee, K. Y. C. Proteins: Struct., Funct., Bioinf. 2008, 72 (1), 1-24. (20) Arispe, N.; Pollard, H. B.; Rojas, E. Proc. Natl. Acad. Sci. U.S.A. 1996, 93 (4), 1710-1715. (21) Lashuel, H. A.; Lansbury, P. T. Q. Rev. Biophys. 2006, 39 (2), 167-201. (22) Sokolov, Y.; Kozak, J. A.; Kayed, R.; Chanturiya, A.; Glabe, C.; Hall, J. E. J. Gen. Physiol. 2006, 128 (6), 637-647. (23) de Planque, M. R. R.; Raussens, V.; Contera, S. A.; Rijkers, D. T. S.; Liskamp, R. M. J.; Ruysschaert, J.-M.; Ryan, J. F.; Separovic, F.; Watts, A. J. Mol. Biol. 2007, 368 (4), 982-997. (24) Yip, C. M.; Elton, E. A.; Darabie, A. A.; Morrison, M. R.; McLaurin, J. J. Mol. Biol. 2001, 311 (4), 723-734. (25) Okada, T.; Ikeda, K.; Wakabayashi, M.; Ogawa, M.; Matsuzaki, K. J. Mol. Biol. 2008, 382 (4), 1066-1074.

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oxidation,26,27 and metal ions28,29 can also play an important role in Aβ accumulation and toxicity, rendering the study of Aβmembrane interactions extremely difficult. On the other hand, many researchers employed artificial surfaces as model systems to study the aggregation and conformational changes of Aβ because these artificial surfaces can not only mimic certain important surface properties of cell membranes but also decouple many key factors (surface hydrophobicity, electrostatics, roughness) to examine these effects on Aβ aggregation separately.10 Self-assembled monolayers (SAMs) are ideal platforms for the study of protein adsorption because of the wide varieties of surface functionalities and the large, uniform atomic-resolution domain. Although all these studies described above agree that the presence of both artificial and biological surfaces induces a conformational transition from random coil to β-structure and therefore accelerates Aβ aggregation,30-32 structural and energetic details of Aβ-surface interactions that control the adsorption and aggregation behaviors of Aβ remain elusive. Molecular dynamics (MD) simulations are well-suited to the study of protein/peptide adsorption and its conformation change on surfaces and provide molecular-level information, which is complementary to experimental observations. In this work, we performed MD simulations to study the effect of surface chemistry of the SAMs on adsorption behavior and conformational change of preformed Aβ17-42 pentamer upon binding to the SAMs. The Aβ17-42 pentamer was used because Aβ42 peptides preferred to aggregate into pentamer and hexamer units at the early assembly of Aβ42 oligomerization,33,34 which is different from Aβ40 oligomerization existed as monomers, dimers, trimers, and tetramers. Moreover, similar atomic structures of Aβ pentamer observed by others,35,36 our previous MD simulations37,38 showed that Aβ17-42 pentamer was very stable in solution, and thus it can be used as an initial configuration to interact with SAMs for examining conformational changes upon the adsorption on the SAMs. Two alkanethiol SAMs on Au(111) were used including hydrophobic methyl S(CH2)11CH3 (CH3-SAM) and hydrophilic alcohol S(CH2)11OH (OH-SAM). Six Aβ-SAM models consisting of three different Aβ orientations on CH3SAM or OH-SAM (Figure 1) were designed to examine the effects of surface chemistry on the adsorption behavior of Aβ peptides and their underlying driving forces. For comparison, Aβ behavior in the bulk solution was also studied. Simulation results showed that Aβ orientation, SAM surface hydrophobicity, and interfacial waters all determine Aβ adsorption behavior on the surface. (26) Domenico, P. Ann. N.Y. Acad. Sci. 2008, 1147 (Mitochondria and Oxidative Stress in Neurodegenerative Disorders), 70-78. (27) Liu, L.; Komatsu, H.; Murray, I. V. J.; Axelsen, P. H. J. Mol. Biol. 2008, 377 (4), 1236-1250. (28) Zatta, P.; Drago, D.; Bolognin, S.; Sensi, S. L. Trends Pharmacol. Sci. 2009, 30 (7), 346-355. (29) Chen, T.; Wang, X.; He, Y.; Zhang, C.; Wu, Z.; Liao, K.; Wang, J.; Guo, Z. Inorg. Chem. 2009, 48 (13), 5801-5809. (30) Lin, M.-S.; Chiu, H.-M.; Fan, F.-J.; Tsai, H.-T.; Wang, S. S. S.; Chang, Y.; Chen, W.-Y. Colloids Surf., B 2007, 58 (2), 231-236. (31) Choucair, A.; Chakrapani, M.; Chakravarthy, B.; Katsaras, J.; Johnston, L. J. Biochim. Biophys. Acta 2007, 1768 (1), 146-154. (32) Wang, Z.; Zhou, C.; Wang, C.; Wan, L.; Fang, X.; Bai, C. Ultramicroscopy 2003, 97 (1-4), 73-79. (33) Bitan, G.; Kirkitadze, M. D.; Lomakin, A.; Vollers, S. S.; Benedek, G. B.; Teplow, D. B. Proc. Natl. Acad. Sci. U.S.A. 2003, 100 (1), 330-335. (34) Urbanc, B.; Cruz, L.; Yun, S.; Buldyrev, S. V.; Bitan, G.; Teplow, D. B.; Stanley, H. E. Proc. Natl. Acad. Sci. U.S.A. 2004, 101 (50), 17345-17350. (35) Zhao, J. H.; Liu, H. L.; Liu, Y. F.; Lin, H. Y.; Fang, H. W.; Ho, Y.; Tsai, W. B. J. Biomol. Struct. Dyn. 2009, 26 (4), 481-490. (36) Miller, Y.; Ma, B.; Nussinov, R. Biophys. J. 2009, 97 (4), 1168-1177. (37) Zheng, J.; Jang, H.; Ma, B.; Tsai, C.-J.; Nussinov, R. Biophys. J. 2007, 93 (9), 3046-3057. (38) Zheng, J.; Ma, B.; Chang, Y.; Nussinov, R. Front. Biosci. 2008, 13 (1), 3919-3930.

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Figure 1. Snapshots of Aβ on the SAMs at 0 and 30 ns of simulations. Labeled residues (a, b, d, e) and all residues in the bottom peptide (c, f) are used to measure the Aβ-SAM distance.

A possible adsorption mechanism is discussed to explain different Aβ adsorption behaviors on hydrophobic and hydrophilic surfaces (Figure 7). This work may provide parallel insights into the interactions of Aβ with lipid bilayers for comparison. It should be noted that the large conformational changes (i.e., peptide folding and self-assembling process) leading to the amyloid aggregation is beyond the scope of this work.

Simulation Methods Aβ Model. Initial monomer coordinate of Aβ17-42 peptide was extracted and averaged from 10 NMR structures (PDB code 2BEG), derived from quenched hydrogen/deuterium-exchange NMR.39 The Aβ17-42 monomer consists of two β-strands, (39) Luhrs, T.; Ritter, C.; Adrian, M.; Riek-Loher, D.; Bohrmann, B.; Dobeli, H.; Schubert, D.; Riek, R. Proc. Natl. Acad. Sci. U.S.A. 2005, 102 (48), 17342-17347.

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β1 (residues V17-S26) and β2 (residues I31-A42), connected by a U-bent turn spanning four residues N27-A30. D23 and K28 form an intrastrand salt bridge to stabilize this β-hairpin structure, in which D23 is located at the N-terminal β-strand region while K28 at the turn region. An Aβ17-42 pentamer was constructed by packing Aβ17-42 monomers on top of each other in a parallel and register manner (Figure 1), with an initial peptide-peptide separation distance of ∼4.7 A˚, corresponding to the experimental data.39 There is no translation applied to one peptide relative to the other. The N- and C-termini were blocked by acetyl and amine groups, respectively. SAM Surface. Two types of self-assembled monolayers (SAMs) on Au(111), hydrophobic methyl S(CH2)11CH3 (CH3SAM) and hydrophilic alcohol S(CH2)11OH (OH-SAM), were used to study their interactions with Aβ peptides. The force field parameters for these two SAMs were adopted from polarizable ether parameters in the CHARMM top_all35_ethers.rtf file, developed by Vorobyov and co-workers.40 Each SAM surface consists of 196 thiol √chains, √ which are densely packed in a 14  14 array, forming a ( 3  3)R30° lattice structure with a sulfursulfur spacing of 4.995 A˚, consistent with electronic diffraction and scanning tunneling microscopy studies of alkanethiol monolayers on Au(111).41,42 The SAM surface has a dimension of 60.56 A˚  69.93 A˚ in the xy plane. All thiol chains have an initial zigzag configuration and were tilted by ∼30° from the surface (i.e., z axis) toward their next-nearest neighbors. MD Protocol. Each system consists of Aβ pentamer, SAMs, explicit waters, and couterions. Aβ pentamer was initially placed at ∼4.5 A˚ above the SAMs to mimic final adsorption state. We are not probing the whole adsorption procedure of Aβ peptides from random coils in aqueous solution to β-structures on the SAMs in this work. Three typical Aβ orientations relative to the SAMs were considered: the hydrophobic C-terminal β-strand region facing to the CH3-SAM or the OH-SAM (referred as the CH3-C model or the OH-C model), the hydrophilic N-terminal β-strand region facing to the CH3-SAM or the OH-SAM (the CH3-N model or the OH-N model), and both β-strands of the hairpin in contact with the CH3-SAM or the OH-SAM (the CH3-U model or the OH-U model). All three orientations have the β-sheets parallel to the surface, consistent with the experimental observation.16,43 This distance was defined by the average separation between the mass center of side chains of characteristic residues (i.e., Ile31, Met35, and Ile41 for the C-terminus orientation, Val18, Glu22, and Ser26 for the N-terminus orientation, and all residues for the U-bend orientation, labeled residues in Figure 1) and the topmost heavy atoms of the SAM. At this distance, the hydration layers from the peptide and the surface are expected to overlap. All MD simulations were performed using the NAMD software package44 with CHARMM27 force field.45 Each system was (40) Vorobyov, I.; Anisimov, V. M.; Greene, S.; Venable, R. M.; Moser, A.; Pastor, R. W.; MacKerell, A. D. J. Chem. Theory Comput. 2007, 3 (3), 1120-1133. (41) Widrig, C. A.; Alves, C. A.; Porter, M. D. J. Am. Chem. Soc. 2002, 113 (8), 2805-2810. (42) Takano, H.; Kenseth, J. R.; Wong, S.-S.; O’Brie, J. C.; Porter, M. D. Chem. Rev. 1999, 99 (10), 2845-2890. (43) Zhang, L.; Zhong, J.; Huang, L.; Wang, L.; Hong, Y.; Sha, Y. J. Phys. Chem. B 2008, 112 (30), 8950-8954. (44) Kale, L.; Skeel, R.; Bhandarkar, M.; Brunner, R.; Gursoy, A.; Krawetz, N.; Phillips, J.; Shinozaki, A.; Varadarajan, K.; Schulten, K. J. Comput. Phys. 1999, 151 (1), 283-312. (45) MacKerell, A. D.; Bashford, D.; Bellott, M.; Dunbrack, R. L.; Evanseck, J. D.; Field, M. J.; Fischer, S.; Gao, J.; Guo, H.; Ha, S.; Joseph-McCarthy, D.; Kuchnir, L.; Kuczera, K.; Lau, F. T. K.; Mattos, C.; Michnick, S.; Ngo, T.; Nguyen, D. T.; Prodhom, B.; Reiher, W. E.; Roux, B.; Schlenkrich, M.; Smith, J. C.; Stote, R.; Straub, J.; Watanabe, M.; Wiorkiewicz-Kuczera, J.; Yin, D.; Karplus, M. J. Phys. Chem. B 1998, 102 (18), 3586-3616.

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solvated with a TIP3P water box with a margin of at least 20 A˚ from top edge of the water box to any Aβ atoms. The systems were then neutralized by adding Cl- and Naþ ions to mimic ∼200 mM ionic strength. The resulting systems were subjected to a series of minimizations using the CHARMM program. Each system was minimized for 1000 steepest decent steps, where the protein backbone atoms were harmonically constrained, sulfur atoms were fixed, and water molecules and counterions were allowed to move, followed by additional 3000 conjugate gradient minimization, where only sulfur atoms were fixed while other atoms were movable. The production MD simulations were performed using an isothermal-isochoric (NVT, T = 300 K) ensemble under periodic boundary conditions with the minimum image convention. All sulfur atoms were fixed to maintain the √ √ ( 3  3)R30° lattice structure of SAMs, and all covalent bonds involving hydrogen were constrained using the RATTLE method during simulations. 2 fs time step was used in the velocity Verlet integration. van der Waals (VDW) interactions were calculated by the switch function with a twin-range cutoff at 12 and 14 A˚. Long-range electrostatic interactions were calculated using the force-shifted method with a 14 A˚ cutoff. The force-shifted method was shown to perform well in both protein and DNA systems.46,47 Structures were saved every 2 ps for analysis. All analyses were performed using tools within the CHARMM and VMD48 packages and code developed in-house.

Results and Discussion To avoid redundant terminology, each Aβ-SAM system is denoted by the type of SAM surface, followed by which region of Aβ pentamer facing to the SAM. For example, the CH3-C system signifies the C-terminal region of Aβ pentamer facing to the CH3-SAM. Analysis of Aβ Adsorption Behavior on the SAM. Analysis of the distance and orientation of Aβ peptides relative to the SAM surface, coupled with MD trajectories, can provide quantitative details of Aβ adsorption/desorption behavior. Figure 1 shows MD snapshots of Aβ pentamer residing on the CH3-SAM and the OH-SAM with three different orientations at 0 and 30 ns of simulations. Figure 2 shows the time evolution of Aβ-SAM distance along the z axis. With different Aβ orientations on the SAM surface, different characteristic residues with side chains outward-pointing toward the SAM surface are selected to measure the Aβ-SAM distance (Figure 1, labeled residues). In the case of Aβ C-terminal regions facing to the SAM, the Aβ-SAM distance is measured between Cβ atoms of Ile31, Met35, and Ile41 and the topmost carbon atoms of methyl group in the CH3-SAM or oxygen atoms of hydroxyl groups in the OH-SAM. Similarly, for the Aβ N-terminal oriented to the SAM, Val18, Glu22, and Ser26 are selected since these three residues are almost evenly distributed along the N-terminal β-strands, while for the Aβ U-bend orientation, only bottom peptide is selected (Figure 1, peptide colored as orange). To quantify the extent of the orientation and rotation of Aβ on the SAM surfaces, two β-strand vectors are defined by one pointing from Val18 to Glu22 at the N-terminus and the other pointing from Ile31 to Met35 at the C-terminus. The averaged angle between the vector normal to β-strand vectors and z axis (i.e., normal to the SAM surface) is used to characterize the Aβ orientation on the SAM surface (46) Beck, D. A. C.; Armen, R. S.; Daggett, V. Biochemistry 2005, 44 (2), 609-616. (47) Norberg, J.; Nilsson, L. Biophys. J. 2000, 79 (3), 1537-1553. (48) Humphrey, W.; Dalke, A.; Schulten, K. J. Mol. Graphics 1996, 14 (1), 33-38.

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Figure 2. Distance between the SAM and Aβ with (a) C-terminal region, (b) N-terminal region, and (c) both N-/C-terminal regions of the hairpin in contact with the SAM.

Figure 3. Aβ orientation on (a) the CH3-SAM and (b) OH-SAM surfaces. 0° represents no change in the initial Aβ orientation relative to the SAM.

(Figure 3), where 0° represents no change in the initial Aβ orientation relative to the SAM. Adsorption Behavior of Aβ Pentamer on the CH3-SAM. It can be seen that when the hydrophobic C-terminal β-strands of Aβ pentamer face the CH3-SAM surface (the CH3-C model), Aβ pentamer was tightly bound to the CH3-SAM during the 30 ns simulation (Figure 1a). All residues at the C-terminal β-strand regions were able to retain their initial positions, as indicated by almost constant distances between Ile31-SAM (5.1 A˚), Met35SAM (4.8 A˚), and Ile41-SAM (4.5 A˚) (Figure 2a). Aβ pentamer slightly rotated ∼3.8° from its initial orientation with respect to the SAM (Figure 3a). Overall, the stable adsorption behavior of the Aβ on the CH3-SAM can be attributed to strong hydrophobic interactions between C-terminal residues of Ile31, Met35, Val 39, Ile41, and Ala42 of the Aβ pentamer and methyl groups of the CH3-SAM. For the CH3-N system, Figure 2b shows that at the first 5 ns all three characteristic distances between Val18, Glu22, and Ser26 and the SAM increased sharply to ∼14 A˚, indicating that Aβ pentamer lost initial contacts with the SAM at this period. However, during the rest of simulation, Glu22 and Ser26 residues gradually moved toward the SAM while Val18 residues continuously moved away from the SAM. This fact suggests that most of residues at the N-terminal β-strands lost their contacts with the CH3-SAM due to weak hydrophobic interactions at the interface, while only residues near the turn regions (Val24, Ser26, and Asn27) retained contacts with the SAM. Consistently, visual inspection of MD trajectory also shows that Aβ pentamer was gradually rotated by lifting its two tails more oriented toward the aqueous solution while marginally attaching the turn regions to the SAM (Figure 1b). For the CH3-U system, it is very interesting to observe from MD trajectory that at the first 2.5 ns Aβ pentamer tended to remain its initial orientation; from 2.5 to 7.5 ns, Aβ pentamer fluctuated between initial orientation and tilted orientation driving the C-terminal β-strand regions to approach the SAM; after 7.5 ns, whole Aβ pentamer rapidly rolled over by ∼71° (Figure 3a), Langmuir 2010, 26(5), 3308–3316

completely changing its orientation from initial bottom peptide contacting with the SAM to C-terminal β-strands facing to the SAM (similar to the CH3-C system), and the new orientation remained steadily until the end of the 30 ns simulation (Figure 1c). The reorientation of Aβ on the hydrophobic SAM surface can be attributed to the competing interactions between hydrophobic C-terminal regions and hydrophilic N-terminal regions with the SAM. Although both hydrophobic C-terminus and hydrophilic N-terminus of the bottom Aβ peptide were initially in contact with the SAM, dominant hydrophobic interactions between C-terminus and the SAM drove Aβ pentamer to adopt more energetically favorable orientation to adsorb on the SAM surface via the C-terminus. During the reorientation process, all peptides were still able to stack together without peptide dissociation. Overall, for the hydrophobic CH3-SAM, three Aβ-SAM systems displayed different adsorption scenarios, suggesting that Aβ peptides have a preferred orientation to adsorb on the hydrophobic CH3-SAM, mainly driven by hydrophobic interactions between the Aβ C-terminus and the CH3-SAM. Adsorption Behavior of Aβ Pentamer on the OH-SAM. Although Aβ pentamer was able to adsorb on the OH-SAM via the C-terminal region similar to the CH3-C system, it is noticeable that the C-terminal β-strands near the OH-SAM were very mobile (Figure 1d), in which four residues of Met35, Val39, Ile41, and Ala42 in the other four peptides were slightly rotated away from the OH-SAM (Figure 2a), leading to the loss of hydrophobic contacts at the interface and therefore relative weak association between the Aβ and the OH-SAM as compared to the CH3-C system. It appears that Aβ requires relative long time to search more energetically favorable sites for adsorption by slightly rotating whole Aβ pentamer on the SAM surface and adjusting its C-terminal side-chain conformations. With the U-bend orientation, visual inspection of MD trajectory showed that at the first 20 ns simulation Aβ pentamer was able to retain its position and orientation on the OH-SAM, but after 20 ns Aβ pentamer was gradually reoriented by ∼40° to allow its C-terminal region in contacts with the OH-SAM. The reorientation of Aβ from U-bend to C-terminal region facing to the SAM surface is similar to the CH3-U model, further confirming that Aβ is more likely to be adsorbed on both SAMs (see CH3-C, OH-C, CH3-U, and OH-U models) via the hydrophobic C-terminus driven by hydrophobic interactions. In the case of the OH-N system, unlike the CH3-N system where Aβ was marginally attached to the SAM surface via the turn region, the exchange of surface hydrophobicity drove Aβ pentamer to completely desorb from the OH-SAM within 10 ns (Figure 1e). Comparison of both CH3-N and OH-N systems suggests that regardless of SAM surface hydrophobicity, Aβ pentamer is not likely to adsorb on the SAM surface through the hydrophilic N-terminus. Overall, a preferential Aβ orientation is a key factor that governs Aβ DOI: 10.1021/la903070y

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adsorption on the SAM, driven by hydrophobic interactions at the interface. Interactions of Aβ Pentamer with the CH3-SAM and the OH-SAM. Comparison among various Aβ-SAM systems reveals different adsorption behaviors of Aβ peptides on the SAM surface, strongly depending on Aβ orientation and surface hydrophobicity. To further understand the physical driving forces underlying the adsorption/desorption of Aβ peptides on the SAM surface, we analyzed interaction energies between Aβ and SAM (Figure 4a,b), where interfacial waters are identified if oxygen atoms of waters are within 6 A˚ of carbon atoms of methyl groups in the CH3-SAM or oxygen atoms of hydroxyl groups in the OH-SAM. Overall, the changes in the interactions between CH3-SAM and Aβ peptides showed opposite trends compared with those interactions between OH-SAM and Aβ peptides, in which Aβ

Figure 4. Interaction energies between (a) CH3-SAM and Aβ, (b) OH-SAM and Aβ, (c) CH3-SAM and interfacial water, and (d) OH-SAM and interfacial water.

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pentamer-CH3-SAM interactions became increasingly favorable while Aβ pentamer-OH-SAM interactions became less favorable (Figure 4a,b). Specifically, the averaged Aβ-SAM interactions from the last 5 ns simulations were -107.6 ( 5.3 kcal/mol (the CH3-C), -54.9 ( 4.0 kcal/mol (the CH3-N), -73.7 ( 5.4 kcal/mol (the CH3-U), -68.8 ( 11.1 kcal/mol (the OH-C), 0.0 kcal/mol (the OH-N), and -71.9 ( 11.1 kcal/mol (the OH-U). The CH3-C system has the most favorable Aβ-SAM interactions resulting in Aβ adsorption on the CH3-SAM, while the OH-N system has no interactions between the Aβ and the OHSAM leading to no Aβ adsorption. These data are qualitatively consistent with the previous geometrical analysis of Aβ distance and orientation relative to the SAM. Regardless of Aβ orientation, Aβ peptides generally suffered the larger energy fluctuation on the OH-SAM than on the CH3-SAM, further highlighting the important role of hydrophobic interactions in Aβ adsorption on the SAM. It should be noted that except for the OH-N model, regardless of the differences in the initial orientation of Aβ and the surface hydrophobicity of SAMs, Aβ always tends to interact with the SAMs via the hydrophobic C-terminal fragments driven by attractive forces between Aβ and the SAMs. This fact suggests that although Aβ peptides can be adsorbed on both hydrophobic and hydrophilic surfaces, the hydrophobic C-terminal fragments appear to be the major interaction sites for adsorption. Binding energy differences among various Aβ-SAM systems also imply that the adsorption kinetics and structural morphology of Aβ could be different on different SAMs. Since the C-terminal β-strands is so important for Aβ adsorption, it is also of interest to compare the relative contributions between C-terminal β-strands and SAM vs between N-terminal β-strands and SAM to the Aβ adsorption, especially for the CH3-U and OH-U systems since with the U-bend Aβ orientation, hydrophobic C-terminus and hydrophilic N-terminus were almost equally in contact with the SAM at the beginning of simulations. It can be seen that for the CH3-U system the C-terminus-SAM interaction curve was almost identical to the total Aβ-SAM interaction curve, while the N-terminus-SAM interactions became negligible after 5 ns (Figure 5c), indicating that major contribution to the Aβ-SAM interactions comes from

Figure 5. Comparison of interaction energies between N-terminal strands (residues 17-26) and the SAM and between C-terminal strands (residues 31-42) and the SAM for the (a) CH3-C, (b) CH3-N, (c) CH3-U, (d) OH-C, (e) OH-N, and (f) OH-U systems.

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Table 1. Summary of Simulation Systems with Averaged Aβ Structural Propertiesa system

rmsd (A˚)

Rg (A˚)

twist (deg)b

status

Table 2. Self-Diffusion Coefficient (D) and Residence Time (τ) of Waters near the SAMs and in Bulk Solutiona system

D (10-5 cm2/s)

τ (ps)

3.9 8.6 adsorbed CH3-C 3.1 ( 0.2 15.2 ( 0.1 13.7 7.6 marginally adsorbed CH3-N 5.2 ( 0.2 14.7 ( 0.1 17.0 9.5 reoriented CH3-U 4.8 ( 0.2 14.2 ( 0.1 OH-C 4.5 ( 0.2 14.6 ( 0.1 14.7 9.1 adsorbed OH-N 4.6 ( 0.2 14.1 ( 0.1 18.8 8.0 desorbed OH-U 3.7 ( 0.3 14.4 ( 0.1 9.1 9.7 reoriented bulk 6.1 ( 0.3 14.7 ( 0.1 17.9 9.9 a All data were averaged from the last 10 ns simulations. b Twist angles are listed for the C-terminal β-strands (left column) and for the Nterminal β-strands (right column).

1.13 30.4 CH3-C 1.32 31.1 CH3-N 1.35 31.7 CH3-U OH-C 0.59 69.9 OH-N 0.68 65.8 OH-U 0.70 68.8 bulk 3.13 18.3 a Interfacial waters are defined by a separation distance of 6 A˚ within the topmost heavy atoms of the SAM, while bulk waters are defined by all waters in the systems.

the C-terminus. Unbalanced interactions between C-/N-terminus and the CH3-SAM drive Aβ pentamer to reorientation itself to form new contacts with the SAM via the C-terminus. Consistently, for the OH-U system, interaction energies through the C-terminus are much more competitive and favorable than those through the N-terminus (Figure 5f). After ∼20 ns, there are no interactions between N-terminal fragments and OH-SAMs, indicating that Aβ is reoriented to contact with the SAMs from initial U-bend orientation to C-terminal orientation. In all systems excluding two barely adsorption systems (CH3-N and OH-N), major contribution to Aβ-SAM interactions comes from the C-terminal β-strand region, independent of initial Aβ orientation. Taken together, although all six Aβ-SAM systems displayed different adsorption scenarios (Figure 1 and Table 1), SAM surface hydrophobicity and preferential Aβ orientation are key factors to control Aβ adsorption; i.e., it appears that C-terminal fragments of Aβ represent a dominant interface for adsorption on the SAM, and the CH3-SAM has the lower energy barrier for peptide adsorption than the OH-SAM. Role of Interfacial Waters in Aβ Adsorption. Physical adsorption of proteins on the surface can be affected by many factors including the chemical and structural properties of surface (charge distribution, surface hydrophobicity, and packing density), the nature of adsorbed proteins (size, shape, sequence, and conformation), and the structural and dynamic behavior of hydration water near the surface. Previous analysis of Aβ-SAM interactions has revealed a correlation between Aβ adsorption and SAM surface hydrophobicity/Aβ orientation. Moreover, interfacial water molecules can also play an important role in Aβ adsorption on the SAM. As can be seen in Figure 4c,d, interactions of interfacial waters with hydrophilic OH-SAM are much more favorable than those of waters with hydrophobic CH3-SAM, indicating that there is a tightly bound water layer adjacent to the OH-SAM instead of the CH3-SAM. As a result, the strong attractive forces between interfacial waters and the OH-SAM via hydrogen bonds create a physical and energy barrier to prevent Aβ adsorption. In contrast, the nonpolar nature of the CH3-SAMs is unable to accommodate water molecules to form a strong hydration layer around CH3-SAM chains. Thus, when Aβ pentamer is brought closer to the hydrophobic CH3-SAMs, the strong hydrophobic interactions between the Aβ and the CH3-SAMs may easily drive the pentamer to adsorb on the surface. Our simulation results are in good agreement with the experimental observations that the hydrophobic SAMs enhance protein adsorption, whereas neutral hydrophilic SAMs reduce protein adsorption.49-51

To further provide insights into the dynamics and mobility of interfacial waters and relate their properties to interactions with the SAM and protein, self-diffusion coefficient (SDC) and residence time (τ) of waters are calculated to quantify the affinity between interfacial waters and the SAM. Interfacial waters were defined by a separation distance of 6 A˚ within the topmost heavy atoms of the SAM. As shown in Table 2, the averaged SDCs of interfacial waters near both CH3-SAM and OH-SAM were ∼1.28  10-5 and ∼0.63  10-5 cm2/s, significantly smaller than that of all waters in the systems (3.13  10-5 cm2/s). Similarly, interfacial waters stay much longer τ on both CH3-SAM (∼31.2 ps) and OH-SAM (∼65.8 ps) surfaces than all waters in the systems (∼18.3 ps). As expected, interfacial waters near the polar OH-SAM have longer residence time and smaller SDC than those near the CH3-SAM, indicating that the OH-SAM surface interacts more strongly with water than the CH3-SAM due to the formation of hydrogen bonds.52 These results are consistent with a number of experimental and simulation works on the structure and dynamics of water near the interface.53-55 Ravinath et al. measured surface diffusivities of waters on the lipids with SDC = (0.9-1.1)  10-5 cm2/s using NMR, and Weng et al.54 reported that the lateral diffusivities of flexible three-centered (F3C) waters are 2.40  10-5 and 0.962  10-5 cm2/s for the CH3-SAM and OH-SAM. All these data imply that a highly hydrated surface can effectively affect protein/peptide adsorption. Conformational Change of Aβ Pentamer on Different SAM Surfaces. It is interesting to compare the conformation change of Aβ peptides on different SAM surfaces. The rootmean-square derivation (rmsd) can be used to characterize the overall conformational changes of the protein. Figure 6a shows the time evolution of backbone RMSDs for Aβ pentamer on SAM surfaces and in bulk solution. It can be seen that the structural deviation of Aβ pentamer was strongly dependent on the Aβ-SAM interfaces. The averaged rmsd values of Aβ were 3.1 A˚ (the CH3-C model), 5.2 A˚ (CH3-N), 4.8 A˚ (CH3-U), 4.5 A˚ (OH-C), 4.6 A˚ (OH-N), and 3.7 A˚ (OH-U) (Figure 1 and Table 1). The CH3-C and OH-U models experienced the least structural deviations during the 30 ns simulations due to strong hydrophobic interactions at the interface. But, in the cases of hydrophilic N-terminals facing to the SAM, Aβ structures in both CH3-N and OH-N models displayed relative large conformational changes. Thus, a larger conformational change of Aβ appears to be generally correlated with the weaker Aβ-SAM interactions (Figure 4). Additionally, the residue-based root-mean-square

(49) Zheng, J.; Li, L.; Chen, S.; Jiang, S. Langmuir 2004, 20 (20), 8931-8938. (50) Zheng, J.; Li, L.; Tsao, H.-K.; Sheng, Y.-J.; Chen, S.; Jiang, S. Biophys. J. 2005, 89 (1), 158-166. (51) Chen, S.; Zheng, J.; Li, L.; Jiang, S. J. Am. Chem. Soc. 2005, 127 (41), 14473-14478.

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(52) Rocchi, C.; Rita Bizzarri, A.; Cannistraro, S. Chem. Phys. 1997, 214 (2-3), 261-276. (53) Kausik, R.; Han, S. J. Am. Chem. Soc. 2009, in press (DOI: 10.1021/ ja9060849). (54) Yang, A. C.; Weng, C. I. J. Chem. Phys. 2008, 129 (15), 154710. (55) He, Y.; Chang, Y.; Hower, J. C.; Zheng, J.; Chen, S.; Jiang, S. Phys. Chem. Chem. Phys. 2008, 10 (36), 5539-5544.

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Figure 6. Aβ structural characterization and comparison on the SAM surface and in bulk solution for (a) backbone rmsd and (b) residue-based backbone RMSF.

fluctuation (RMSF) of backbone atoms was measured from their average positions to assess the local dynamical variation of the peptides (Figure 6b). The RMSF profile shows that residues near the turn and the N-/C-terminal regions exhibited a higher flexibility than those in the β-strand regions. Comparison of the rmsd and RMSF profiles indicates that the edge and loop residues are the primary contributions to the overall conformational changes in Aβ pentamer. In all models, all Aβ pentamers were still able to maintain overall structure and local secondary structure (i.e., the β-strand-turn-β-strand motif), indicating that the SAM surfaces did not induce significantly the association of Aβ pentamer. Comparison to Aβ Pentamer in Bulk Solution. It is also interesting to compare the structures of Aβ oligomer on the SAM surfaces with that of in bulk solution. The comparison of Aβ structure in bulk solution with those on the SAM surfaces shows some similarities and interesting discrepancies. First, as a general feature Aβ pentamer displays a higher degree of dynamics in bulk water than on the SAM surfaces, in which Aβ pentamer in bulk solution experienced the largest structural deviation (∼6.1 A˚) and residue fluctuation (Figure 6), which could be attributed to the loss of side-chain contacts between peptide and the SAM. Second, all Aβ pentamers display different extents of β-strand twisting regardless of whether or not the SAM surface is presented. Two twist angles were used to characterize β-strand twisting at both C-terminus and N-terminus by averaging all angles between two neighboring vectors connecting the CR atoms from Phe19 to Val24 at the N-terminus and from Leu34 to Val39 at the C-terminus, where 0° represents no twisting between adjacent peptides. Similarly, Aβ in bulk solution experienced relatively larger β-strand twisting than those on the SAM surfaces (Table 1). Combining the results of β-strand twisting with the interaction data shows that Aβ appears to be more twisted in aqueous solutions or under weak surface interactions. Strong interactions between Aβ and the surface and two-dimensional surface-confined area will restrict side chain movement and therefore suppress the twisting of β-strands, like the CH3-C and OH-U systems. This is also confirmed by comparing the differences in β-strand twisting at both C-terminus and Nterminus (Table 1) and in interactions of C-/N-terminus with the SAM (Figure 5). Third, although different SAM surfaces induce different extents of conformational changes in Aβ pentamer, Aβ pentamer can still remain its parallel in-register integrity, intrastrand salt bridges between Asp23 and Lys28, and β-strand-loop-β-strand motifs during 30 ns simulations for all systems, indicating that Aβ pentamer remains stable on the SAMs and in solution. Biological Implications. Our simulations have several important implications to the Aβ adsorption on the surface. First of all, Aβ can be adsorbed on both hydrophobic and hydrophilic 3314 DOI: 10.1021/la903070y

Figure 7. Schematic representation of Aβ adsorption on the hydrophobic and hydrophilic surfaces. (A to B) “Solution-state” monomers are incorporated into existing “surface-bound” oligomers on the CH3-SAM through end-to-end stacking, forming relative uniform linear aggregates. (C to D to E) There are three possible pathways for Aβ adsorption and aggregation on the OH-SAM. First, two weakly “surface-bound” oligomers are merged into a large oligomer; second, “surface-bound” oligomer is desorbed from the surface to the solution where they interact with “solution-state” monomers/oligomers to form a new oligomer; third, “solution-state” monomers are added to the “surfacebound” oligomers, similar to the adsorption mechanism on the CH3-SAM.

surfaces via different Aβ fragments and orientations. Overall, Aβ peptides are much easier to be adsorbed on the CH3-SAM than the OH-SAM (the CH3-C vs OH-C and CH3-N vs OH-N). Undoubtedly, contacts of a hydrophobic C-terminus with the CH3-SAM surface are more energetically favorable than those of C-terminus with the OH-SAM or N-terminus with the CH3-SAM. McMasters and co-workers14 studied the aggregation and adsorption of Aβ10-35 peptides on different alkanethiol monolayers using AFM and reflection-absorption infrared spectroscopy. They found that highly hydrophobic fluoromethyl HS-(CH2)2-(CF2)7-CF3 induces much more Aβ aggregates than hydrophilic HS-(CH2)11-OH by a factor of 10, indicating that hydrophobic surface can dramatically promote Aβ aggregation or seed formation as compared to hydrophilic one, and the preferred orientation of Aβ with respect to different SAMs allows for fast amyloid aggregation. Second, because of the physicochemical differences of the surfaces, Aβ aggregates may adopt distinct structural morphologies (size and shape) via different adsorption mechanisms. As shown in Figure 7, there are two possible pathways for Aβ aggregation on the hydrophilic surface. Our simulations have showed that Aβ peptides are very mobile on the hydrophilic surface due to weak surface affinity. Thus, those weakly adsorbed Aβ peptides can easily associate with each other to form larger assemblies on the surface. Alternatively, these weak “surfacebound” Aβs are desorbed from the surface to the bulk solution where they interact with “solution-state” monomers or oligomer to form large aggregates and then deposited back onto the surface. Because of relative flexible association modes in solution and on the surface, it is expected that Aβ aggregates display a wide range of structural morphologies on the hydrophilic surface. Unlike hydrophilic surface, Aβ oligomers can barely move around once they are adsorbed on the hydrophobic surface due to strong surface affinity. Therefore, it is the most likely that “solution-state” monomers/oligomers are incorporated into Langmuir 2010, 26(5), 3308–3316

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existing “surface-bound” oligomers through end-to-end stacking,56 forming relative uniform linear aggregates. Kowalewski et al.11 observed that on hydrophilic mica Aβ formed particulate, pseudomicellar aggregates at low Aβ concentration and linear aggregates at high concentration, while on hydrophobic graphite Aβ formed uniform, elongated β-sheets with less than ∼100 nm in length and ∼1 nm in height. Regardless of Aβ orientation and surface hydrophobicity, Aβ peptides can always grow along two directions of parallel and perpendicular to the fibril axis, but competitive assembly via fibril elongation and lateral association often leads to different structural morphologies. It should be noted that due to time-scale limitation in MD simulations, the proposed model do not consider the conformational change from random coil to β-structure upon binding to the surface. Third, from our study, interfacial waters can also affect Aβ adsorption on the surface. Our previous experiments and simulations49-51,55,57 showed that tightly bound water layer near the hydrophilic surface can form a physical and energetic barrier via hydrogen bonds to prevent direct contact between proteins and the surface. Conversely, the dehydration of the hydrophobic surface and the nonpolar part of Aβ makes them very easily to interact with each other because the interfacial water molecules cannot form hydrogen bonds with either the hydrophobic surface or the nonpolar part of Aβ. Finally, comparison of Aβ adsorption on the SAMs and on the lipid bilayers shows some interesting similarity and discrepancies. First, Yip et al.17 found that repulsive forces between the hydrophilic lipid head groups and the hydrophobic C-terminus of Aβ1-42 prevent the insertion of the peptide into the bilayer and favor surface binding. Choucair et al.31 and Koppaka et al.58 also reported that the accumulation of Aβ on gel phase domains of DPPC/DOPC bilayers and DMPC bilayers does not appear to lead to the insertion of Aβ into the membrane. Similarly, we did not observe and expect from our simulations that Aβ peptides would penetrate into the SAMs because the spacing distance of 4.995 A˚ between neighboring SAM chains is too small to allow the side chains of Aβ (at least 3.0 A˚ for nonaromatic residues and 5.0 A˚ for aromatic residues) to insert into the SAMs due to the steric effect. However, in contrast to the lack of insertion of Aβ into membranes, several studies have demonstrated that C-terminal fragments of Aβ peptide are prone to penetrate into membrane to induce a significant apoptotic cell death,59-61 highlighting the importance of C-terminal fragments in mediating membrane structures, in good agreement with our simulation results that C-terminal fragments have strong binding interactions with both CH3-SAM and OH-SAM surfaces. Second, Choucair and co-workers31 reported that Aβ peptides are prone to aggregate on rigid and ordered gel phase domains, rather than the fluid phase. Our simulations showed that SAM chains were also rigid and ordered structures as evidenced by very small RMSDs (rmsd < 0.6 A˚ for the CH3-SAMs and rmsd < 1.2 A˚ for the OH-SAMs), as well as barely changed tilt angles of ∼30°

(56) Collins, S. R.; Douglass, A.; Vale, R. D.; Weissman, J. S. PLoS Biol. 2004, 2 (10), e321. (57) Li, L.; Chen, S.; Zheng, J.; Ratner, B. D.; Jiang, S. J. Phys. Chem. B 2005, 109 (7), 2934-2941. (58) Koppaka, V.; Axelsen, P. H. Biochemistry 2000, 39 (32), 10011-10016. (59) Demeester, N.; Baier, G.; Enzinger, C.; Goethals, M.; Vandekerckhove, J.; Rosseneu, M.; Labeur, C. Mol. Membr. Biol. 2000, 17 (4), 219-228. (60) Mingeot-Leclercq, M.-P.; Lins, L.; Bensliman, M.; Van Bambeke, F.; Van Der Smissen, P.; Peuvot, J.; Schanck, A.; Brasseur, R. Chem. Phys. Lipids 2002, 120 (1-2), 57-74. (61) Stehanie, R.; Olivier, S.; Olivier, S.; Annick, T.; Robert, B.; Alain, M. Protein Sci. 2005, 14 (5), 1181-1189. (62) Zhou, J.; Zheng, J.; Jiang, S. J. Phys. Chem. B 2004, 108 (45), 17418-17424.

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Article Table 3. Structural Characterization of SAM Chains system

SAM rmsd (A˚)

tilt anglea (deg)

0.60 ( 0.01 32.6 ( 0.3 CH3-C 0.40 ( 0.01 32.6 ( 0.3 CH3-N 0.16 ( 0.01 32.7 ( 0.3 CH3-U OH-C 0.86 ( 0.33 29.4 ( 0.5 OH-N 1.16 ( 0.19 30.4 ( 0.6 OH-U 1.15 ( 0.21 29.6 ( 0.5 a Tilt angle is calculated by averaging all angles between the vector from sulfur atom to the topmost heavy atom of carbon atom for CH3SAM or oxygen atom for OH-SAM and the normal vector of SAM surface (z axis).

(Table 3), consistent with previous MD simulations of lysozyme and cytochrome c on the SAMs.49,50,62,63 It should be noted that due to the complex nature of neuronal cell membrane and the notorious sensitivity of Aβ aggregation to experimental conditions, experimental studies of Aβ-membrane interactions associated with Aβ aggregation and toxicity show large inconsistent data.64 A number of researchers18,65-67 reported that soluble oligomers increase membrane conductance by thinning cell membrane, lowering dielectric barrier, and increasing ionic leakage. They all did not observe the formation of discrete ion-channel or the insertion of peptides. In contrast, the other group of researchers2,68-70 showed that amyloid oligomers form cation-selective pores/channels in neuronal plasmas membrane. These channels are very similar to the antibacterial pore-forming toxins. Moreover, enriched cholesterols in membranes can act as major binding sites for overexpressing Aβ production and accelerating Aβ aggregation,24,25,71 contributing to the neuronal death.72,73 Despite these discrepancies, it appears that the composition and physiochemical properties of the surfaces including neuronal membranes, SAMs, and mica/ graphite govern the outcomes of Aβ-surface interactions such as Aβ binding structure, aggregation, and toxicity.

Conclusions We have carried out all-atom molecular dynamics simulations to investigate the interactions of Aβ17-42 pentamer with two model self-assembled monolayers: hydrophobic CH3-SAM and hydrophilic OH-SAM, particularly focusing on the effects of surface chemistry and Aβ orientation on the adsorption behavior of Aβ peptides and their underlying driving forces. Comparison among six Aβ-SAM systems reveals different adsorption behaviors of Aβ peptides on the SAM surface, strongly depending on Aβ orientation, surface hydrophobicity, and interfacial water. Preferential Aβ orientation can optimize peptide-surface interactions and reduce search space for adsorption, while sur(63) Trzaskowski, B.; Leonarski, F.; Les, A.; Adamowicz, L. Biomacromolecules 2008, 9 (11), 3239-3245. (64) Eliezer, D. J. Gen. Physiol. 2006, 128 (6), 631-633. (65) McLaurin, J.; Chakrabartty, A. J. Biol. Chem. 1996, 271 (43), 26482-26489. (66) Demuro, A.; Mina, E.; Kayed, R.; Milton, S. C.; Parker, I.; Glabe, C. G. J. Biol. Chem. 2005, 280 (17), 17294-17300. (67) Valincius, G.; Heinrich, F.; Budvytyte, R.; Vanderah, D. J.; McGillivray, D. J.; Sokolov, Y.; Hall, J. E.; Loche, M. Biophys. J. 2008, 95 (10), 4845-4861. (68) Arispe, N.; Pollard, H. B.; Rojas, E. Proc. Natl. Acad. Sci. U.S.A. 1993, 90 (22), 10573-10577. (69) Quist, A.; Doudevski, I.; Lin, H.; Azimova, R.; Ng, D.; Frangione, B.; Kagan, B.; Ghiso, J.; Lal, R. Proc. Natl. Acad. Sci. U.S.A. 2005, 102 (30), 10427-10432. (70) Arispe, N.; Diaz, J. C.; Simakova, O. Biochim. Biophys. Acta 2007, 1768 (8), 1952-1965. (71) Lin, M.-S.; Chen, L.-Y.; Wang, S. S. S.; Chang, Y.; Chen, W.-Y. Colloids Surf., B 2008, 65 (2), 172-177. (72) Wray, S.; Noble, W. J. Neurosci. 2009, 29 (31), 9665-9667. (73) Nicholson, A. M.; Ferreira, A. J. Neurosci. 2009, 29 (14), 4640-4651.

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face-terminated functionalities can mediate the dynamics and structure of interfacial waters, producing a low-energy barrier for Aβ adsorption. Although Aβ can be adsorbed on both hydrophobic and hydrophilic surfaces, it appears that Aβ hydrophobic C-terminal fragments may represent a dominant interface for adsorption on the SAM and the CH3-SAM has a lower energy barrier for Aβ adsorption than the OH-SAM, hightlighting the importance of hydrophobic interactions at the interface. We add a cautious remark that no protein kinetic factors were considered in

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the work because of the time-scale limitations. Ongoing studies of conformational changes from random coil to β-structure of Aβ monomer will provide more complete and detailed information on Aβ adsorption and aggregation on the SAM surface. Acknowledgment. This work is supported by American Chemical Society Petroleum Research Fund (48188-G5) and 3M Nontenured Faculty Award. This study utilized the high performance Biowulf PC cluster at the Ohio Supercomputer Center.

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