[Molecular Medicine and Medicinal Chemistry] Alzheimer's Disease: Insights into Low Molecular Weight...

November 26, 2012 10:1 9in x 6in Alzheimer’s Disease: Insights Into Low Molecular … b1377-chB2

2Probing the Stability of Fibril

and Tubular Species UsingAll-Atom Molecular Dynamics

Simulations in Solution:Insight into Polymorphism

Yifat Miller∗,†, Buyong Ma‡ and Ruth Nussinov‡,§

2.1 Introduction

Alzheimer’s disease (AD) is the most common cause of dementia. Solubleβ-amyloid oligomers (Aβ) formed by Aβ40/Aβ42 peptides are the likelycausative or major AD agents. Aβ40/Aβ42 peptides are characterized by theirtendency to aggregate into β-sheet-rich amyloid fibril. Increasing evidencefrom studies in human, transgenic mice, cultured cells, wild-type rodents,

∗Center for Cancer Research Nanobiology Program, NCI-Frederick, Frederick, MD 21702,USA.†Department of Chemistry, Ilse Katz Institute for Nanoscale Science and Technology, Ben-Gurion University of the Negev, Be’er Sheva 84105, Israel.‡Basic Science Program, SAIC-Frederick, Inc., Center for Cancer Research NanobiologyProgram, NCI-Frederick, Frederick, MD 21702, USA.§Sackler Institute of Molecular Medicine, Department of Human Genetics and MolecularMedicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. Tel: +1-301-846-5579; Fax: +1-301-846-5598; E-mail: [email protected].

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240 Y. Miller, B. Ma and R. Nussinov

and in vitro systems indicates that soluble oligomers of Aβ40/Aβ42 are bothresponsible for amyloidosis (Kirkitadze et al., 2002; Walsh and Selkoe, 2004)and are the toxic agent (Hardy and Selkoe, 2002; Bitan, 2006). Some datasuggest that their final large aggregates can also lead to cytotoxicity (Luhrset al., 2005; Yoshiike et al., 2007).

Over the last decades, experimental and computational approacheshave revealed structural details of various Aβ organizations. To date, thekey question of the mechanism through which amyloids lead to cytotoxityis still a major challenge. The self-assembly mechanism leading to orderedfibril formation is still not fully understood either. Open questions relateto (i) how the monomeric peptides assemble into oligomers; (ii) whichsegments of a long peptide constitute the recognition motifs and, as such,play key roles in amyloid fibril formation; (iii) how the β-strands arrangerelative to one another; (iv) is there a favored organization between theβ-sheets and, if so, as one would expect, (v) what is it and what are theintermolecular interactions between the layers that stabilize the favoredamyloid fibril organization(s); and finally, (vi) what are the pathways andintermediate states involved in seed and fibril formation? These combine tocontribute to one of the most difficult issues related to protein aggregation,i.e. aggregate polymorphism; the aggregates can have different preferredfibril architectures depending on (even slight) changes in any of thesesequence or environmental factors.

Studies of polymorphism are important; understanding the range ofpotential conformations under various conditions and the self-assemblymechanism by which ordered fibrils assemble from the conformationalensemble may assist in designing effective drugs. Computationally, molec-ular dynamics (MD) simulations are a useful tool to address amyloidconformational variability (Ma and Nussinov, 2006a). Solid-state nuclearmagnetic resonance (ssNMR) data of Aβ segments coupled with atomisticMD simulations have further been useful in addressing the driving forcesfor targeted associations.

This chapter focuses on polymorphic Aβ conformations. It compilesvarious conformations of Aβ1-42/Aβ1-40 and their fragments. It alsopresents studies of polymorphic Aβs using all-atom MD simulations insolution and structural features that affect the architectures of fibril and oftubular species.

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Probing the Stability of Fibril and Tubular Species 241

2.2 Molecular Structures Underlying β-Amyloid Polymorphism

The structural regularity of amyloids is not as good as that of thehighly ordered crystals; nonetheless, X-ray fibril diffraction has providedimportant structural features. All amyloids, regardless of their sequencesand secondary structures in the native folded states, convert to β-sheets.The β-strand backbone orientation is perpendicular to the fibril axis,which is termed cross-β-structure. The distance between the β-strandsis ∼0.5 nm, permitting favorable backbone hydrogen bonds, and the layersare usually separated by ∼1 nm allowing closely packed β-sheet association(Sikorski et al., 2003). With these basic features unchanged, the amyloidpolymorphism derives from the way that the β-strands associate into fibriland tubular species. There are three major structural features that maydecide the overall amyloid fibril morphologies: (i) differences in backboneorientation; (ii) differences in backbone conformation; and (iii) differencesin the way in which the oligomers — with almost identical structures —associate. The combination of these three factors can give rise to anenormous variation in conformational detail and, consequently, in seedoligomer and fibril morphology.

2.2.1 Fibril species

Polymorphic fibrils differ by backbone organization within and betweenβ-sheets, backbone turns, and association of β-sheet oligomers (Milleret al., 2010a). This section discusses these structural features in a context ofpolymorphism.

In principle, there are thousands of possible patterns of intra- andinter-residue amyloid fibril backbone strand organizations for in-registerand out-of-register interactions. Figure 2.1 highlights several representativein-register alignments with double-layered β-strand segment arrangementswithin and between sheets.

Short segments are more convenient systems, as their smaller sizesmake them easier to study experimentally and computationally; at thesame time the basic principles are likely to be unchanged. Most of thestudied Aβ segments (Gorevic et al., 1987; Balbach et al., 2002; Petkova et al.,2006) are organized in an in-register, parallel arrangement; however, somepresent a preferred antiparallel organization (enumerated in Table 2.1).

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Figure 2.1. Potential architectures of strand organizations in amyloid fibrils. Interactions(as dotted lines) are shown between the first layer (blue) and the second layer (red) for (a)parallel to parallel, face-to-face orientation; (b) parallel to parallel, face-to-back orientation;(c) parallel to antiparallel, face-to-face orientation; (d) parallel to antiparallel, face-to-back orientation; (e) antiparallel to antiparallel, face-to-face orientation, parallel to parallelbetween layers; (f) antiparallel to antiparallel, face-to-back orientation, parallel to parallelbetween layers; (g) antiparallel to antiparallel, face-to-back orientation, parallel to paral-lel between layers; and (h) antiparallel to antiparallel, face-to-back orientation, antiparallelto antiparallel between layers. This figure is taken from Miller et al. (2010a).

Although only some of the potential organizations have been observed,others may also exist, but their populations may be too low to be observedby experiment.

Short fragments (less than 15 residues in length) tend to haveantiparallel β-strands. Based on X-ray diffraction and Ala16Aβ1-28 mutantsubstitution comparison, the β-strands’ orientation of Aβ1-28 fibrils wasproposed to be all-antiparallel (as in Fig. 2.1h) (Kirschner et al., 1987).Aβ11-25 has antiparallel β-strands within the sheet; however, the sheet–sheet

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Table 2.1. Features of the full-length β-amyloid (Aβ) and its fragments. References foreach segment are detailed in Miller et al. (2010a).

Hydrophobic Hydrophilic Charged Net charge ConformationNumber of residues residues residues of of amyloid

Segment residues (%) (%) (%) monomer fibril

Aβ1-42/ 40/42 48 40 21 −3 ParallelAβ1-40

Aβ10-35 26 46 42 19 −1 ParallelAβ17-42 26 62 19 12 −1 ParallelAβ14-23 10 50 50 30 −1 AntiparallelAβ34-42 9 78 0 0 0 AntiparallelAβ1-28 28 32 61 32 −3 AntiparallelAβ16-22 7 71 29 29 0 AntiparallelAβ11-25 15 47 47 27 −2 AntiparallelAβ1-9 9 22 67 44 −2 Disorder

(randomcoil)

Aβ24-30 7 29 43 14 +1 Loop

orientation is parallel (as in Fig. 2.1g) (Sikorski et al., 2003). For Aβ14-23, theantiparallel conformation has also been proposed from nuclear magneticresonance (NMR) data (Chen et al., 2005). For Aβ16-22, which is one ofthe most studied fragments, both experimental and computational studiessuggest antiparallel organization (Ma and Nussinov, 2002a,b; Santini et al.,2004; Lu et al., 2009). In the C-terminal region, Aβ34-42 was also shown byssNMR to be antiparallel (Lansbury et al., 1995). Infrared (IR) spectroscopyindicates that amyloid fibrils of Aβ29-42 and Aβ10-23 have antiparallel β-sheet and a less ordered structure (loops or β-turns) (Hilbich et al., 1991).

Polymorphism can thus arise from different β-strand orientationand side-chain registration. For example, Aβ16-22 can have two stableantiparallel orientations (Fig. 2.1g and h) (Ma and Nussinov, 2002a), whichboth have in-register side-chain interactions. Recent experiments alsorevealed an out-of-register, one residue shift in the antiparallel orientation(Liang et al., 2008). Aβ25-35, a central Aβ region fragment, may have bothparallel and antiparallel orientations; both arrangements are stabilized byhydrophobic interactions (Ma and Nussinov, 2006a). However, the parallelorientation could be more ordered due to a strong steric zipper match of

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the central Ile residues; Ile was proposed to promote amyloid formation ingeneral (Ma and Nussinov, 2007).

Full-length and other long Aβ fragments, especially those con-taining central and C-terminal regions (e.g. Aβ10-35), mostly have parallelβ-strand orientation. However, the tendencies for a U-turn backboneconformation in the central region provide yet another variable feature forAβ peptides. The flexibility of the turn region allows the Aβ peptide to adoptslightly different turn types leading to different amyloid morphologies.

Two models of the three-dimensional structures of Aβ1-42/Aβ1-40

fibrils were proposed and verified experimentally (Ma and Nussinov2006b). The first, the Ma–Nussinov–Tycko model, (Ma and Nussinov2006b; Petkova et al. 2006) presents a double-layer structure with residues10-22 and 30-40 forming β-strands and residues 23-29 forming a bend orloop. The two β-strands form two separate, in-register, parallel β-sheets,which can interact with one another due to the intervening bend segment.The second model by Luhrs et al. (2005) presents a parallel single-layerstructure of Aβ1-42 fibrils based on hydrogen/deuterium exchange NMRdata, combined with side-chain packing constraints from pairwise muta-genesis, ssNMR, and high-resolution cryo-electron microscopy (cryoEM)(Protein Data Bank code, 2BEG). Observations based on these experimentsindicated that residues 1-16 are structurally disordered and residues 17-26and 31-42 form two β-strands, β1 and β2, respectively, connected by a U-turn spanning four residues, 27-30. This model also suggested that paralleloligomers associate in parallel. The differences between the two U-turns areas follows. First, the U-turn in the Ma–Nussinov–Tycko model is tighter,thus allowing the C-terminal residues to interact with up to N-terminalresidue Tyr10 (Ma and Nussinov, 2006b; Petkova et al., 2006); however, theLuhrs’ turn is looser, with Lys28 shifted and consequently the C-terminalregion can only reach residue Leu17 (Luhrs et al., 2005). Second, thedisordered segment in Tycko’s model includes eight residues, whereas inLuhrs’ it is 16, as the N-terminal projects into the solvent much beyondthe C-terminal; thus, without tight van der Waals (vdW) interactions. Thisalso affects the sheet–sheet registration. Thus, polymorphism in parallelAβ1-42/Aβ1-40 (or fragments that include the U-turn segment and the twoβ-strands, such as Aβ10-35) appears to be largely governed by the U-turnconformational variability and an interplay between various factors can

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also be expected to play a role in polymorphism. Consistently, a combinedexperimental and simulation study revealed varied U-turn shapes formedby different segment sizes: Aβx-42(x = 29-31) (Wu et al., 2009). Recentsimulations presented variations for Aβ10-40/10-42 (Huet and Derreumaux,2006) and Aβ1-42 (Lam et al., 2008; Melquiond et al., 2008; Masman et al.,2009) due to the U-turn conformation.

Apart from the large structural variations described above, smallchanges in side-chain orientation or in the environment (e.g. pH, tempera-ture, concentration, salt, agitation, synthetic vs. brain-seeded) may leadβ-sheet oligomers to associate in different ways, leading to amyloid poly-morphism with similar molecular organizations. This has been illustratedin Aβ1-40 fibril morphologies. Recently, polymorphism of Aβ1-40 at theprotofibril level has been obtained by Meinhardt et al. (2009).

2.2.2 Tubular species

Paravastu et al. (2008) presented two Aβ1-40 fibril morphologies differingin several features: the overall symmetry (two-fold vs. three-fold); theconformation of the non-β-strand (U-turn/loop) segment; and the qua-ternary contacts. Paravastu et al. (2009) have shown that the predominantfibril structure in the brain obtained by seeding with Aβ1-40 brain-derivedoligomers (Fig. 2.2) differs from the structure of purely synthetic fibrilsthat were previously characterized (Petkova et al., 2006; Paravastu et al.,2008). Miller et al. (2011) investigated the three-fold symmetry fibrilusing all-atom MD simulations. Preliminary results indicate that the three-fold symmetry fibril has a cavity along the fibril axis. Among the fibrilforms, a recent cryoEM study revealed a unique structure of Aβ1-42 fibrilswith a tubular shape and a cavity (Zhang et al., 2009). Using all-atomMD simulations in explicit solvent, Miller et al. (2010c) interpreted thecryoEM density map of Aβ1-42 by examining two main possibilities of thearrangement of the C-termini along the main fibril axis: the first, withC-termini facing the internal fibril cavity, and the second, with C-terminifacing the external surface of the fibril (Fig. 2.3). The simulations revealedthat, when the C-termini face the external surface of the fibril, the cavityexists along the simulations, whereas when the C-termini face the internal

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Figure 2.2. Experiment-based structural models of Aβ9-40. (a) A ribbon presentation ofthe lowest-energy model for fibrils with twisted morphology. (b) Atomic representation,viewed down the fibril axis. Hydrophobic, polar, negatively-charged, and positively-chargedamino acid side-chains are green, magenta, red, and blue, respectively. Backbone nitrogenand carbonyl oxygen atoms are cyan and pink. (c) Comparison of twisted (upper) andstriated ribbon (lower) fibril morphologies in negatively transmission electron microscopyTEM images. (d) Atomic representation of a model for striated ribbon fibrils developedpreviously by Petkova et al. (2005, 2006). Reprinted with permission from Paravastu et al.(2009). Copyright 2009 National Academy of Sciences, USA.

surface of the fibril, the hydrophobic effect involving interactions betweenresidues at the C-termini leads to fibril collapse.

Apart from the tubular species, Aβ annular species are also possible andhave larger pores than tubular species. Recently, all-atom MD simulationstudies revealed annular species, which also play a role as ion channels(Zheng et al., 2008; Jang et al., 2009, 2010).

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Figure 2.3. The fitting of the model shown in (c) to the cryoEM density map (Zhanget al., 2009). The experimental cryoEM density map (yellow) was generated from theProtein Nanoscale Architecture by Symmetry (PNAS) program (Miller et al., 2010c). (a)Top view and (b) side view: coordinates for Aβ17-42 were extracted from Luhrs et al. (2005)(Protein Data Bank: 2BEG) and fragments 1-16 were linked to the L17 of each monomer byforming intermolecular hydrophobic interactions between F4 (yellow) in the N-termini ofone 12-mer and G29 (blue) in the loop regions of a second 12-mer (c). Top view (d) and sideview (e) of the two-fold axial symmetry of the simulated cryoEM map of the model shownin (c) at a resolution of 10 Å, generated by the PNAS program. The continuous helix of thesimulated cryoEM map (e) of the model shown in (c) is in agreement with the experimentalcryoEM map (f).

2.3 Stability and Polymorphism can be Affected by Sequenceand Physiochemical Properties

The β-sheet in Aβ segments, although defined by interstrand hydrogenbonding, owes its stability mainly to intra- and intersheet side-chainpacking (Lopez de la Paz et al., 2002). Some of the Aβ peptide segmentsadopting β-strand conformations form amyloid fibrils in a parallelorientation and others in an antiparallel orientation (Table 2.1). Obviously,it is not only the length that determines the stability of the fibril, but alsothe nature of the residues along the segment that interacts. This sectionexamines the properties of these fragments that can affect their preferredarchitecture, such as segment length, hydrophobicity, hydrophilicity, andcharge.

The percentage of hydrophobic residues is above 40% for all β-strandsegments presented here, and some of these segments are also enrichedin hydrophilic residues (Table 2.1). There are two hydrophobic-rich

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regions in Aβ1-40/Aβ1-42 peptides, segments 17-22 (KLFFA) and 30-42(AIIGLMVGGVVIA). ssNMR indicates that Aβ10-35, Aβ1-40, and Aβ1-42

fibrils are organized in parallel, whereas Aβ16-22, Aβ34-42, and Aβ14-23 areantiparallel. Most of these consist of hydrophobic segments believed to becrucial for aggregation (Inouye et al., 1993; Serpell, 2000).

Hydrophobic interactions are the driving force for protein–proteinassociation, including protein aggregation (Ma and Nussinov, 2007); theylargely control the stability and therefore determine the organization. Inβ-sheets, stabilization by hydrophobic interactions could maximize whenthe interactions are between stacked identical residues, which is the case ina parallel organization (Tsai et al., 2006). For example, fifteen interactionsbetween in-register hydrophobic residues of two β-strands stabilize theparallel organization of Aβ10-35, whereas there are only six interactionsbetween hydrophobic residues in the antiparallel organization. Parallelβ-sheet organization juxtaposes the hydrophobic segments of neighboringpeptide chains, whereas an antiparallel organization does not. Therefore,the preferred orientation of the β-strands for Aβ10-35 is parallel.

Hydrophobic interactions are non-specific, which could underlie thediversity of possible interaction patterns. Therefore, amyloids dominatedby hydrophobic interactions could easily present polymorphic behavior. Inthe case of Aβ16-22, an in-register antiparallel organization has been shownto be preferred. However, a new arrangement with one residue shifted andthe backbone flipped is possible under acidic conditions (Liang et al., 2008).Apart from the role of the hydrophobic effect in the polymorphic characterof the β-strand arrangement within β-sheets, the diversity of hydrophobicinteractions between protofibrils can also contribute to amyloid polymor-phism. In the case of Aβ1-40, the highly hydrophobic C-terminal regionprovides many possible interaction interfaces for two-fold or three-foldarrangement patterns (Paravastu et al., 2008; Meinhardt et al., 2009).

Electrostatics can play a crucial role in Aβ fibrils (Kirschner et al.,1987; Tjernberg et al., 2002). At first glance, the charged nature of manyamyloid-forming peptides can increase the solubility and thus decreasetheir intrinsic ability to form β-sheet-based aggregates. However, in certaincases, charged residues may help the peptides to form amyloids, as indicatedby the full-length Aβ peptide, which forms ordered fibrils much more easilythan the shorter and more hydrophobic aggregative Aβ17-42.

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Table 2.1 provides the net charge of the segments. Some Aβ segmentshave β-strands that are negatively charged, some are positively charged, andothers have a net charge of zero. It appears that β-strand organization inparallel or antiparallel does not depend on the segment net charge. Thepercentage of the charged residues in the segment does not determine thearrangement of the β-strands either. However, charge–charge interactionsbetween sheets are important for fibril formation and residues withcomplementary charges promote fibril formation. Therefore, the positionsof the charged residues along the sequence of the segment are importantfor the stabilization of the amyloid fibril and affect the arrangement of theβ-strands.

As hydrophobic interactions are non-specific, the attractive electro-static interactions limit the variability of amyloid arrangements. TheAβ11-25 fragment is a good example. Compared with Aβ1-40, the Aβ11-25

fragment can form a fibril that yields better quality and higher resolutionX-ray diffraction data (Sikorski et al., 2003), indicating lower fibrilstructural diversity. Expanded from Aβ16-22, the charged pattern in Aβ11-25

increases the weight of electrostatic interactions compared with the(unchanged) hydrophobic interactions. In the N-terminus, two His residues(His13, His14) increase the positive charge in the Lys16 region, whereasAsp23 added to Glu22 leads to a more negative C-terminus. As a result, thestrong electrostatic interactions make the in-register antiparallel alignmentof Aβ11-25 highly favorable. Clearly, the strong electrostatic interactioncontributed to the structural uniformity of the Aβ11-25.

The preferred fibril architecture is also stabilized by tight vdW packingbetween β-sheets. Steric zippers (i.e. tight packing) appear to be a genericstructural motif of the amyloid protofilament (Balbirnie et al., 2001; Nelsonet al., 2005), as good geometrical fit provides favorable vdW interactionsand constrains side-chain movement.

2.4 Polymorphism in Metal-Binding Sites in β-Amyloids

The most prevalent metal ions in biological systems, such as Zn2+, Cu2+,and Fe3+, are known to be essential for normal brain function anddevelopment (Danks, 1988; Pollitt, 2000). Disrupted cellular homeostasisof these ions is thought to play a central role in the aggregation and

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neurotoxicity of Aβ (Bartzokis, 2004; Huang et al., 2004). These metalions are markedly enriched in Aβ plaques (Bush et al., 1994; Stoltenberget al., 2007) and may act as seeding factors. In contrast, although a higherconcentration of Al3+ has been established in the brain of AD patients(Candy et al., 1986; Walton, 2006), the mechanism of its pathogenesis inAD is still debated (Zatta et al., 2003). Nonetheless, experiments clearlydemonstrated that Al3+ ions do play a role in Aβ aggregation and inneurotoxicity (Drago et al., 2008).

So far, Aβ binding sites for Zn2+ and Cu2+ have been studied ext-ensively, but there is a lack of data for Fe3+. Polymorphism can be obser-ved in Cu2+ complexes with Aβ. Possible Cu2+ coordinating residuesinclude histidines (His6, His13, His14), tyrosine (Try10), aspartate orglutamate (Asp1, Glu3, Asp7, Glu11, Glu22, Asp23), methionine (Met35),deprotonated amides of peptide backbone, or carbonyl groups (Liu et al.,1999; Hou and Zagorski, 2006; Hureau et al., 2009). The most commonresidues are located at the N-terminus of Aβ; the binding site for Cu2+was proposed to consist of the three histidines (His6, His13, and His14)and Tyr10 (Curtain et al., 2001; Mantri et al., 2008). Further, studiesdemonstrated that the Cu2+ binding site can involve Asp1 (Syme et al.,2004; Streltsov et al., 2008) or Glu11 (Streltsov et al., 2008). A recent studyof the Cu2+ binding site in the rat Aβ1-28 fragment revealed that Cu2+binds to Asp1, His6, and His14 (Gaggelli et al., 2008a). His13 is absent inrat Aβ1-28. Recent simulations suggested that Cu2+ coordinates with His13and His14 of each two Aβ peptides (Han et al., 2008). These studies suggestvarious possible conformers. We therefore conclude that Aβ with differentexperimentally detected Cu2+ binding sites depends on the populations ofthe various morphologies under different conditions.

The zinc binding site in Aβ is also located at the disordered N-terminal(Asp1–Lys16). Seven potential N-terminal residues can bind Zn2+: Asp1,Glu3, His6, Asp7, Glu11, His13, and His14. As for the Cu2+ binding site,in the case of Zn2+, the three histidines (His6, His13, and His14) at the N-terminal segment coordinate with Zn2+ (Miura et al., 2000; Zirah et al.,2004; Gaggelli et al., 2008b). Recently, three different models of Zn2+binding to Aβ were observed by experiments. First, the NMR structuresof Zn2+–Aβ1-16 in aqueous solution at pH 6.5 and 7.4 showed that Zn2+ isbound to these three histidines and to the two carboxylic groups of Glu11(Zirah et al., 2006). Second, an NMR study on Zn2+–Aβ1-28 in sodium A

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Figure 2.4. The experimental, solution nuclear magnetic resonance-based conformers ofthe Zn2+ complexed with residues 1-16 (the N-terminal region) fit well with the experiment-based structure for the remainder of the Aβ (residues 17-42), and consequently can be linkedto create models of the full-length Aβ1-42 complexed with Zn2+. The Zn2+-coordinated N-terminal coordinates are taken from Zirah et al. (2006), Gaggelli et al. (2008b), and Minicozziet al. (2008). The coordinates of residues 17-42 are taken from the Luhrs oligomers (Luhrset al., 2005). This figure is taken from Miller et al. (2010b).

dodecyl sulfate micelles at pH 7.5 and a temperature of 298 K proposeda tetra-coordination of Zn2+ by His6, Glu11, His14, and Asp1 at theN-terminus for rat Aβ1-28, and penta-coordination of Zn2+ by His6, Glu11,His13, His14, and Asp1 at the N-terminus for human Aβ1-28 (Gaggelliet al., 2008b). The third model is based on X-ray absorption spectroscopyin which Zn2+–Aβ complexes are coordinated with four histidines (His13and His14 of two monomers), indicating that each metal ion is shared bytwo Aβ peptides (Minicozzi et al., 2008). Miller et al. (2010b) constructeda range of potential oligomers of Aβ1-42 complexed with Zn2+ in theN-terminal domain. Several of them are seen in Fig. 2.4. The all-atom MDsimulations revealed stable intra- and intermolecular zinc coordinationin Aβ oligomers. The prevailing organization and the probability ofdetecting certain morphologies depend on experimental conditions such astemperature, Zn2+ concentration, and pH. Oligomer stability also dependson the size, in particular when dealing with Zn2+ in the N-terminal.

2.5 Concluding Remarks and Future Directions

Currently it is increasingly recognized that amyloids present a vast rangeof conformational states. The polymorphic differences may or may not be

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large; polymorphism can be expressed in altered β-strand arrangements,altered turn conformations, altered sheet–sheet registrations, differences inthe locations and fragment sizes of regions that are disordered, differentsheet organizations, and different supramolecular packing. For amyloidpolymorphism, both dominant and minor forms should all be treatedin addressing the mechanism of aggregation and toxicity, as it is alwayspossible that minor species are the toxic agents.

Polymorphism raises a key question: how to prevent AD with drugdesign or other therapeutic approaches. Targeting toxicity in late-stage ADmay miss the reservoir of polymorphic forms; preventing Aβ productionmay encounter side-effects derived from normal Aβ function loss. Whendesigning targeted drugs, various conformations should be considered.Therefore, comprehension of polymorphism using all-atom MD simula-tions coupled with ssNMR data of Aβ is useful in addressing the drivingforces for targeted associations and should assist in therapeutic agentdesign. Using both ssNMR and all-atom MD simulations, we speculatethat future directions will be in progress in the next few years.

Acknowledgments

This project has been funded in whole or in part with Federal funds fromthe NCI, NIH, under contract number HHSN261200800001E. The contentof this publication does not necessarily reflect the views or policies of theDepartment of Health and Human Services, nor does mention of tradenames, commercial products, or organizations imply endorsement by theU.S. Government. This research was supported (in part) by the IntramuralResearch Program of the NIH, NCI, CCR.

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[Molecular Medicine and Medicinal Chemistry] Alzheimer's Disease: Insights into Low Molecular Weight...

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