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Role of Water in Mediating the Assembly of Alzheimer Amyloid-# A#16#22 Protofilaments Mary Griffin Krone, Lan Hua, Patricia Soto, Ruhong Zhou, B

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Role of Water in Mediating the Assembly of Alzheimer Amyloid-# A#16#22 Protofilaments Mary Griffin Krone, Lan Hua, Patricia Soto, Ruhong Zhou, B Subscriber access provided by Columbia Univ Libraries Article Role of Water in Mediating the Assembly of Alzheimer Amyloid-# A#16#22 Protofilaments Mary Griffin Krone, Lan Hua, Patricia Soto, Ruhong Zhou, B. J. Berne, and Joan-Emma Shea J. Am. Chem. Soc., 2008, 130 (33), 11066-11072 • DOI: 10.1021/ja8017303 • Publication Date (Web): 29 July 2008 Downloaded from http://pubs.acs.org on November 18, 2008 More About This Article Additional resources and features associated with this article are available within the HTML version: • Supporting Information • Links to the 1 articles that cite this article, as of the time of this article download • Access to high resolution figures • Links to articles and content related to this article • Copyright permission to reproduce figures and/or text from this article Journal of the American Chemical Society is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published on Web 07/29/2008 Role of Water in Mediating the Assembly of Alzheimer Amyloid- A16-22 Protofilaments Mary Griffin Krone,† Lan Hua,§ Patricia Soto,† Ruhong Zhou,§,| B. J. Berne,§,| and Joan-Emma Shea*,†,‡ Department of Chemistry and Biochemistry, UniVersity of California, Santa Barbara, California 93106, Department of Physics, UniVersity of California, Santa Barbara, California 93106, Department of Chemistry, Columbia UniVersity, New York, New York 10027, and Computational Biology Center, IBM Thomas J. Watson Research Center, 1101 Kitchawan Road, Yorktown Heights, New York 10598 Received March 7, 2008; E-mail: [email protected] Abstract: The role of water in promoting the formation of protofilaments (the basic building blocks of amyloid fibrils) is investigated using fully atomic molecular dynamics simulations. Our model protofilament consists 16 17 18 19 20 21 22 of two parallel -sheets of Alzheimer Amyloid- 16-22 peptides (Ac-K -L -V -F -F -A -E -NH2). Each sheet presents a distinct hydrophobic and hydrophilic face and together self-assemble to a stable protofilament with a core consisting of purely hydrophobic residues (L17,F19,A21), with the two charged residues (K16,E22) pointing to the solvent. Our simulations reveal a subtle interplay between a water mediated assembly and one driven by favorable energetic interactions between specific residues forming the interior of the protofilament. A dewetting transition, in which water expulsion precedes hydrophobic collapse, is observed for some, but not all molecular dynamics trajectories. In the trajectories in which no dewetting is observed, water expulsion and hydrophobic collapse occur simultaneously, with protofilament assembly driven by direct interactions between the hydrophobic side chains of the peptides (particularly between F-F residues). For those same trajectories, a small increase in the temperature of the simulation (on the order of 20 K) or a modest reduction in the peptide-water van der Waals attraction (on the order of 10%) is sufficient to induce a dewetting transition, suggesting that the existence of a dewetting transition in simulation might be sensitive to the details of the force field parametrization. Introduction Amyloid fibrils are comprised of several protofilaments, Proteins play a critical role in most cellular processes, from which consist of two or more layers of -sheets. In the specific case of the Amyloid-beta (A) peptide associated with AD, both signal transduction to enzyme catalysis. Folding to the correct 5 three-dimensional native state is crucial to their function. Under the small and large mature aggregates have shown cytotoxicity, pathological conditions, proteins can misfold, typically to indicating the importance of studying various stages of the fibril structures in which the hydrophobic residues, which form the growth process. The protofilaments grow in two manners, longitudinally, by addition of monomer proteins at their ex- hydrophobic core of the folded protein, are exposed to the 6 7 solvent. These misfolded proteins can self-assemble into a tremities, and laterally, by addition of -sheet layers. This variety of aggregate structures, including large, insoluble fibrillar paper aims at a theoretical investigation of the role of water entities known as amyloids. A number of diseases, including (the “hydrophobic effect”) in mediating the lateral formation Alzheimer’s disease (AD) and type II diabetes, are associated of protofilaments. Although it is well accepted that the with the presence of amyloid. The proteins involved in amyloid hydrophobic effect plays a significant role in protein self- diseases are dissimilar, in both sequence and fold, yet the end assembly in water, the precise mechanism by which it operates, products of aggregation bear striking structural similarities as well as the exact role of water in facilitating this assembly, including a fibrillar structure and cross- X-ray diffraction remains controversial. When two strongly hydrophobic surfaces, pattern.1-3 Because many proteins which are not associated with greater than 1 nm in length (such as would be the case for the disease have been shown to form amyloid fibrils, it has been extended -sheets of a protofilament), are brought together to suggested that under certain conditions, any protein is capable a critical distance, it has been suggested that a dewetting of forming an amyloid.4 transition occurs between the two surfaces and the resulting † Department of Chemistry and Biochemistry, University of California. (4) Dobson, C. M. Trends Biochem. Sci. 1999, 24, 329–332. § Columbia University. (5) Caughey, B.; Lansbury, P. T. Annu. ReV. Neurosci. 2003, 26, 267– | IBM Thomas J. Watson Research Center. 298. ‡ Department of Physics, University of California. (6) Tseng, B. P.; Esler, W. P.; Clish, C. B.; Stimson, E. R.; Ghilardi, (1) Teplow, D. B. Amyloid 1998, 5, 121–142. J. R.; Vinters, H. V.; Mantyh, P. W.; Lee, J. P.; Maggio, J. E. (2) Sunde, M.; Blake, C. AdV. Protein Chem. 1997, 50, 123–159. Biochemistry 1999, 38, 10424–10431. (3) Eanes, E. D.; Glenner, G. G. J. Histochem. Cytochem. 1968, 16, 673– (7) Nichols, M. R.; Moss, M. A.; Reed, D. K.; Lin, W.-L.; Mukhopadhyay, 677. R.; Hoh, J. H.; Rosenberry, T. L. Biochemistry 2002, 41, 6115–6127. 11066 9 J. AM. CHEM. SOC. 2008, 130, 11066–11072 10.1021/ja8017303 CCC: $40.75 2008 American Chemical Society Assembly of Alzheimer Amyloid- Protofilaments ARTICLES vacuum drives the subsequent self-assembly or hydrophobic collapse. This scenario has been anticipated theoretically,8,9 and the critical role of dewetting in the hydrophobic effect has been studied using analytical theories and simulations of simple solutes10-21 as well as simulations of more evolved protein systems.22,23 In general, it is nontrivial for the protein complexes to display a nanoscale dewetting transition, since it requires two or more extended hydrophobic surfaces facing each other. Therefore, it is only anticipated in the final stage of protein complex folding, once each unit has been formed and the final hydrophobic collapse is occurring.22,23 Alternatively, it has been suggested that the role of water in assembly would be “lubrication”: in this scenario, water would not drive assembly but rather facilitate proper packing of the hydrophobic surfaces in the final stages of assembly. Such a lubrication picture has been observed in coarse-grained and fully atomistic simulations of the formation of the hydrophobic core src-SH3 protein.24-26 To the best of our knowledge, the role of water in protofilament assembly, be it related to a dewetting transition, a lubrication effect, or other, has not yet been studied using fully atomistic simulations. Our simulations focus on a model system consisting of the 16 17 18 19 20 21 22 A16-22 peptide (Ac-K -L -V -F -F -A -E -NH2), the shortest fragment of the A peptide capable of aggregating into fibrils. The self-assembly of the A peptide is implicated in Alzheimer’s disease, a debilitating neurodegenerative disease, in which atrophy of the brain leads to functional and behavioral disturbances.27 There is increasing experimental evidence that the production and accumulation of the A peptide is essential to the pathogenesis of AD.28 Figure 1. A16-22 model protofilament. (a and b) The initial structure The A16-22 peptide consists of a purely hydrophobic core used to start the MD trajectory seen in Figure 2b-i, with D0 of 1.28 nm. (LVFFA) flanked by two oppositely charged residues (K and Front (a) and side (b) views are shown. Side chains are colored as follows: E). Solid state NMR experiments by Tycko and co-workers K ) red, L ) orange, V ) yellow, F ) green, A ) blue, and E ) violet. indicate that the peptides comprising the A16-22 protofilament For clarity, only water molecules in the interpeptide region have been shown. (c) The same structure after 1000 ps of unconstrained MD simulation at are oriented in an antiparallel manner, with interpeptide separa- 300 K, started from the structure shown in (a and b). (d) A single A16-22 tion within a -sheet layer of 0.47 nm and an interlayer peptide pair, one from each layer, is isolated from the protofilament shown in (c). (8) Berard, D. R.; Attard, P.; Patey, G. N. J. Chem. Phys. 1993, 98, 7236– 29 7244. separation between two -sheet layers of 0.99 nm. Our earlier (9) Patey, G. N. Ber. Bunsen-Ges. Phys. Chem. 1996, 100, 885–888. computational work on the A16-22 protofilament, using a fully (10) Wallqvist, A.; Berne, B. J. J. Phys. Chem. 1995, 99, 2893–2899. atomic protein model in explicit solvent,30 established that the most (11) Li, X.; Li, J.; Eleftheriou, M.; Zhou, R. J. Am. Chem. Soc. 2006, 128, 12439–47 stable protofilament consists of parallel -sheets composed of anti . 16 (12) Zangi, R.; Hagen, M.; Berne, B. J. J. Am. Chem. Soc. 2007, 129, 4678– parallel A16-22 -strands, such that the charged side chains (K 86. and E22) point toward the solvent, while the L17,F19, and A21 V (13) Lum, K.; Luzar, A.
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