Comparing the folding free‐energy landscapes of Aβ42 variants with different aggregation properties

Mitternacht, Simon; Staneva, Iskra; Härd, Torleif; Irbäck, Anders

doi:10.1002/prot.22775

Cited by 54 publications

(108 citation statements)

References 53 publications

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“…Although there are multiple binding modes of action, the analysis of intermolecular contact maps shows the NQTrp molecule binds strongly to the CHC and FL regions, reducing therefore the strength of the interpeptide interactions among residues 16−35, interactions that are seen in many simulations of Aβ1−40 and Aβ1−42 dimers in the absence of inhibitors. 17,[25][26][27][28][29][30][31][32]45 Our result is also in agreement with a recent hydrogen−deuterium exchange coupled with mass spectrometry study showing that the region of residues 20−35 is the first to aggregate, followed by the region of residues 36−42 and then the region of residues 1−19 during Aβ1−42 oligomerization. 46 At the residual and atomic level, we have determined that the NQTrp molecules bind mostly to the side chains of residues Arg5, Asp7, Tyr10, His13, Lys16, Phe19/Phe20, Lys28, and Leu34/Met35.…”

Section: ■ Discussionsupporting

confidence: 90%

Atomic and Dynamic Insights into the Beneficial Effect of the 1,4-Naphthoquinon-2-yl-l-tryptophan Inhibitor on Alzheimer’s Aβ1–42 Dimer in Terms of Aggregation and Toxicity

Zhang

et al. 2013

ACS Chem. Neurosci.

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Aggregation of the amyloid β protein (Aβ) peptide with 40 or 42 residues is one key feature in Alzheimer's disease (AD). The 1,4-naphthoquinon-2-yl-L-tryptophan (NQTrp) molecule was reported to alter Aβ self-assembly and reduce toxicity. Though nuclear magnetic resonance experiments and various simulations provided atomic information about the interaction of NQTrp with Aβ peptides spanning the regions of residues 12−28 and 17−42, none of these studies were conducted on the fulllength Aβ1−42 peptide. To this end, we performed extensive atomistic replica exchange molecular dynamics simulations of Aβ1−42 dimer with two NQTrp molecules in explicit solvent, by using a force field known to fold diverse proteins correctly. The interactions between NQTrp and Aβ1−42, which change the Aβ interface by reducing most of the intermolecular contacts, are found to be very dynamic and multiple, leading to many transient binding sites. The most favorable binding residues are Arg5, Asp7, Tyr10, His13, Lys16, Lys18, Phe19/Phe20, and Leu34/Met35, providing therefore a completely different picture from in vitro and in silico experiments with NQTrp with shorter Aβ fragments. Importantly, the 10 hot residues that we identified explain the beneficial effect of NQTrp in reducing both the level of Aβ1−42 aggregation and toxicity. Our results also indicate that there is room to design more efficient drugs targeting Aβ1−42 dimer against AD.

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Section: ■ Discussionsupporting

confidence: 90%

Atomic and Dynamic Insights into the Beneficial Effect of the 1,4-Naphthoquinon-2-yl-l-tryptophan Inhibitor on Alzheimer’s Aβ1–42 Dimer in Terms of Aggregation and Toxicity

Zhang

et al. 2013

ACS Chem. Neurosci.

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“…The simulation temperatures are between T 0 and ∼1.2 T 0 , where T 0 denotes the temperature used in our previous monomer study and corresponds to ∼273-278 K in physical units [18]. Our present study focuses primarily on properties at the same temperature T 0 , but we begin with a brief discussion of how the state of aggregation of the systems (WT, F20E, E22G, E22G/I31E) depends on the simulation temperature.…”

Section: Resultsmentioning

confidence: 99%

“…Based on the same computational model, we recently investigated [18] the natively unfolded Aβ42 monomer [19][20][21]. To validate the simulations, we compared calculated NMR properties (J -couplings and chemical shifts) with experimental data (see Methods).…”

Section: Monte Carlo Simulations Of Aβ42 Dimersmentioning

confidence: 99%

Monte Carlo Study of the Formation and Conformational Properties of Dimers of Aβ42 Variants

Mitternacht

Staneva

Härd

et al. 2011

Journal of Molecular Biology

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Small soluble oligomers, and dimers in particular, of the amyloid β -peptide (Aβ) are believed to play an important pathological role in Alzheimer's disease (AD). Here we investigate the spontaneous dimerization of Aβ42, with 42 residues, by implicit solvent all-atom Monte Carlo (MC) simulations, for the wild type (WT) peptide and the mutants F20E, E22G and E22G/I31E. The observed dimers of these variants share many overall conformational characteristics, but differ in several aspects at a detailed level. In all four cases, the most common type of secondary structure is intramolecular antiparallel β -sheets. Parallel in-register β -sheet structure, as in models for Aβ fibrils, is rare. The primary force driving the formation of dimers is hydrophobic attraction. The conformational differences that we do see involve turns centered in the 20-30 region. The probability of finding turns centered in the 25-30 region, where there is a loop in Aβ fibrils, is found to increase upon dimerization and correlate with experimentally measured rates of fibril formation for the different Aβ42 variants. Our findings hint at reorganization of this part of the molecule as a potentially critical step in Aβ aggregation. Over the past decade, atomic-level structural models of Aβ fibrils have been developed [5,6]. In these models, each Aβ molecule participates in two intermolecular face-to-face packed β -sheets, both with a parallel, in-register organization. The two strand regions are connected by a loop at residues ∼25-30 to a β -loop-β motif. This overall fibril organization is shared by the WT variants of both Aβ40 In this article, we investigate the elementary step of Aβ aggregation, the formation of dimers, by implicit solvent all-atom MC methods. We focus on Aβ42, with 42 residues, which is the form of Aβ most closely linked to AD. Starting from random initial conformations, we study the ensembles of dimeric states populated by Aβ42 WT and the three mutants E22G, E22G/I31E and F20E. These The E22G mutation, which is associated with the familial so-called Arctic form of AD [12], is known to enhance aggregation, whereas the F20E mutation has the reverse effect [11]. The double mutant E22G/I31E shows more complex aggregation properties. Its propensity to form fibrils is almost as high as that of the E22G variant, whereas its propensity to form prefibrillar species is only slightly higher than that of the F20E variant [11,13].In previous computational studies of Aβ dimers, one approach has been to examine the stability of preformed structures [14,15]. Also, a first study of spontaneous dimer formation was 2 Monte Carlo simulations of Aβ42 dimersreported [16]. However, simulating the spontaneous dimerization of full-length Aβ molecules is a challenge. Here we tackle this problem by using MC techniques and an effective force field (see Methods). This force field was developed through folding thermodynamics studies of a structurally diverse set of peptides and small proteins, while deliberately keeping it as simple as possi-Based on th...

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“…The hairpin is predicted to comprise residues 17 to 23 and 30 to 36 as antiparallel β-strands connected by a turn involving residues 25 to 29. There is considerable evidence that such a conformation is accessible in monomeric Aβ: (i) it forms in complex with binding proteins (16,17), (ii) its secondary structure elements persistently appear in computer simulations of different Aβ fragments (15,24,25), and (iii) NMR data suggest that turn formation of residues 24 to 28 nucleates monomer folding (26). We previously postulated that metastable Aβ oligomers contain hairpin subunits and that conversion into a related cross-β conformation transforms oligomers into fibril seeds and primes these for the runaway aggregation that is typical of amyloid fibril formation.…”

Section: Discussionmentioning

confidence: 99%

“…Nevertheless, NMR experiments (14) and molecular modeling (15) suggest that the central and C-terminal hydrophobic regions of Abeta have a propensity to form extended beta-strand conformations with a connecting turn between them. Such a "hairpin" conformation (Fig.…”

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confidence: 99%

Stabilization of neurotoxic Alzheimer amyloid-β oligomers by protein engineering

Sandberg

Luheshi²,

Söllvander³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Soluble oligomeric aggregates of the amyloid-β peptide (Aβ) have been implicated in the pathogenesis of Alzheimer's disease (AD). Although the conformation adopted by Aβ within these aggregates is not known, a β-hairpin conformation is known to be accessible to monomeric Aβ. Here we show that this β-hairpin is a building block of toxic Aβ oligomers by engineering a doublecysteine mutant (called AβCC) in which the β-hairpin is stabilized by an intramolecular disulfide bond. Aβ 40 CC and Aβ 42 CC both spontaneously form stable oligomeric species with distinct molecular weights and secondary-structure content, but both are unable to convert into amyloid fibrils. Biochemical and biophysical experiments and assays with conformation-specific antibodies used to detect Aβ aggregates in vivo indicate that the wild-type oligomer structure is preserved and stabilized in AβCC oligomers. Stable oligomers are expected to become highly toxic and, accordingly, we find that β-sheet-containing Aβ 42 CC oligomers or protofibrillar species formed by these oligomers are 50 times more potent inducers of neuronal apoptosis than amyloid fibrils or samples of monomeric wild-type Aβ 42 , in which toxic aggregates are only transiently formed. The possibility of obtaining completely stable and physiologically relevant neurotoxic Aβ oligomer preparations will facilitate studies of their structure and role in the pathogenesis of AD. For example, here we show how kinetic partitioning into different aggregation pathways can explain why Aβ 42 is more toxic than the shorter Aβ 40 , and why certain inherited mutations are linked to protofibril formation and early-onset AD.amyloid-β peptide | protein aggregation | protein structure | protofibril | β-hairpin conformation

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Comparing the folding free‐energy landscapes of Aβ42 variants with different aggregation properties

Cited by 54 publications

References 53 publications

Atomic and Dynamic Insights into the Beneficial Effect of the 1,4-Naphthoquinon-2-yl-l-tryptophan Inhibitor on Alzheimer’s Aβ1–42 Dimer in Terms of Aggregation and Toxicity

Atomic and Dynamic Insights into the Beneficial Effect of the 1,4-Naphthoquinon-2-yl-l-tryptophan Inhibitor on Alzheimer’s Aβ1–42 Dimer in Terms of Aggregation and Toxicity

Monte Carlo Study of the Formation and Conformational Properties of Dimers of Aβ42 Variants

Stabilization of neurotoxic Alzheimer amyloid-β oligomers by protein engineering

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