Yin Luo

Fudan University, Shanghai, Shanghai Shi, China

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Publications (25)136.69 Total impact

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    ABSTRACT: Neuronal calcium sensor 1 (NCS-1) protein has a variety of different neuronal function and interacts with multiple binding partners mostly through a large solvent-exposed hydrophobic crevice (HC). A single R102Q mutation in human NCS-1 protein was demonstrated to be associated with autism disease. Solution NMR study reported that this R102Q mutant had long-range chemical shift effects on the HC and the C-terminal tail (L3). To understand the influence of the R102Q mutation on the HC and L3 of NCS-1, we have investigated the conformational dynamics and the structural flexibility of wild type (WT) NCS-1 and its R102Q mutant by conducting extensive all-atom molecular dynamics (MD) simulations. On the basis of six independent 450-ns MD simulations, we have found that R102Q mutation in NCS-1 protein 1) dramatically reduces the flexibility of loops L2 and L3; 2) facilitates L3 in a more extended state to occupy the hydrophobic crevice to a larger extent; 3) significantly affects the inter-segment salt-bridges; 4) changes the subspace of the free energy landscape of NCS-1 protein. Analysis of salt bridge network in both WT and the R102Q variant demonstrates that the R102Q-mutation-induced salt bridge alternations play a critical role on the reduced flexibility of L2 and L3. These results reveal the important role of salt bridges on the structural properties of NCS-1 protein and that R102Q mutation disables the dynamics relocation of C-terminus, which may block the binding of NCS-1 protein to its receptors. This study may provide structural insights into the autistic spectrum disorder associated with R102Q mutation.
    The Journal of Physical Chemistry B 10/2014; DOI:10.1021/jp507936a · 3.38 Impact Factor
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    ABSTRACT: The pathogenesis of Alzheimer’s disease (AD) is associated with the aggregation of amyloid-β (Aβ) peptides into toxic aggregates with β-sheet character. In a previous computational study, we showed that pristine single-walled carbon nanotubes (SWCNTs) can inhibit the formation of β-sheet-rich oligomers in the central hydrophobic core fragment of Aβ (Aβ16–22). However, the poor solubility of SWCNTs in water hinders their use in biomedical applications and nanomedicine. Here, we investigate the influence of hydroxylated SWCNT, a water-soluble SWCNT derivative, on the aggregation of Aβ16–22 peptides using all-atom explicit-water replica exchange molecular dynamics simulations. Our results show that hydroxylated SWCNTs can significantly inhibit β-sheet formation and shift the conformations of Aβ16–22 oligomers from ordered β-sheet-rich structures toward disordered coil aggregates. Detailed analyses of the SWCNT-Aβ interaction reveal that the inhibition of β-sheet formation by hydroxylated SWCNTs mainly results from strong electrostatic interactions between the hydroxyl groups of SWCNTs and the positively charged residue K16 of Aβ16–22 and hydrophobic and aromatic stacking interactions between SWCNTs and F19 and F20. In addition, our atomic force microscopy and thioflavin T fluorescence experiments confirm the inhibitory effect of both pristine and hydroxylated SWCNTs on Aβ16–22 fibrillization, in support of our previous and present replica exchange molecular dynamics simulation results. These results demonstrate that hydroxylated SWCNTs efficiently inhibit the aggregation of Aβ16–22; in addition, they offer molecular insight into the inhibition mechanism, thus providing new clues for the design of therapeutic drugs against amyloidosis.
    Biophysical Journal 10/2014; 107(8):1930–1938. DOI:10.1016/j.bpj.2014.08.034 · 3.83 Impact Factor
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    ABSTRACT: Tau is an intrinsically disordered protein (IDP) implicated in Alzheimer's disease. Recently, tau proteins were discovered to be able to catalyze self-acetylation, which may promote its pathological aggregation. Understanding the paradox of tau's random-like conformations, aggregation propensity, and enzymatic activity are challenging questions. We characterized the atomic structures of two truncated tau constructs, K18 and K19, consisting of, respectively, only the four- and three-repeats of tau protein, providing structural insights into tau's paradox. Extensive 4.8 μs replica-exchange molecular dynamics simulations of the tau proteins achieved quantitative correlation with experimental Cα chemical shifts. Our results revealed (1) dynamically ordered conformations with close lysine-cysteine distances essential for tau self-acetylation and (2) high β-sheet content and large hydrophobic surface exposure for the two critical hexapeptides ((275)VQIINK(280) and (306)VQIVYK(311)), crucial for tau aggregation. Together, they illuminate tau's perplexing behavior of how its disordered state can accomplish both roles.
    Journal of Physical Chemistry Letters 09/2014; 5(17):3026-3031. DOI:10.1021/jz501457f · 6.69 Impact Factor
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    ABSTRACT: Amyloid deposits are implicated in the pathogenesis of many neurodegenerative diseases such as Alzheimer's disease (AD). The inhibition of β-sheet formation has been considered as the primary therapeutic strategy for AD. Increasing data show that nanoparticles can retard or promote the fibrillation of amyloid-β (Aβ) peptides depending on the physicochemical properties of nanoparticles, however, the underlying molecular mechanism remains elusive. In this study, our replica exchange molecular dynamics (REMD) simulations show that fullerene nanoparticle - C60 (with a fullerene : peptide molar ratio greater than 1 : 8) can dramatically prevent β-sheet formation of Aβ(16-22) peptides. Atomic force microscopy (AFM) experiments further confirm the inhibitory effect of C60 on Aβ(16-22) fibrillation, in support of our REMD simulations. An important finding from our REMD simulations is that fullerene C180, albeit with the same number of carbon atoms as three C60 molecules (3C60) and smaller surface area than 3C60, displays an unexpected stronger inhibitory effect on the β-sheet formation of Aβ(16-22) peptides. A detailed analysis of the fullerene-peptide interaction reveals that the stronger inhibition of β-sheet formation by C180 results from the strong hydrophobic and aromatic-stacking interactions of the fullerene hexagonal rings with the Phe rings relative to the pentagonal rings. The strong interactions between the fullerene nanoparticles and Aβ(16-22) peptides significantly weaken the peptide-peptide interaction that is important for β-sheet formation, thus retarding Aβ(16-22) fibrillation. Overall, our studies reveal the significant role of fullerene hexagonal rings in the inhibition of Aβ(16-22) fibrillation and provide novel insight into the development of drug candidates against Alzheimer's disease.
    Nanoscale 07/2014; 6(16). DOI:10.1039/c4nr01005a · 6.74 Impact Factor
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    ABSTRACT: Alzheimer's disease (AD) is associated with the pathological self-assembly of amyloid-β (Aβ) peptides into β-sheet-rich oligomers and insoluble amyloid fibrils. Experimental studies reported that 1,2-(dimerthoxymethano)fullerene (DMF), a water soluble fullerene derivative, inhibits strongly Aβ peptide aggregation at the early stage. However, the interaction and binding mechanisms are not well understood. In this study, we have investigated the detailed interaction of a DMF molecule with a fibrillar hexamer of full-length Aβ42 and the resulting structural alterations by performing multiple all-atom explicit solvent molecular dynamics (MD) simulations. Starting from different initial states with a minimum distance of 2 nm between the DMF and the Aβ protofibril, our MD simulations show that the DMF binds to the Aβ protofibril via both slow and fast binding process. Three dominant binding sites are identified: the central hydrophobic core (CHC) site (17LVFFA21), turn site (27NKGAI31), and C-terminal β-sheet site consisting of the smallest-sidechain residue Glycine and hydrophobic residues (31IIGLMVGGVVI41). Binding energy analyses reveal the importance of π-stacking interactions, especially in the CHC site, hydrophobic interactions, and curvature matching to binding. Strikingly, we find that the binding of DMF to the turn region can disrupt the D23-K28 salt-bridge that is important for the Aβ fibrillation. These results provide molecular insight into the binding mechanism of fullerene to Aβ protofibrils and offer new routes for the therapeutic drug design using fullerene derivatives against AD.
    The Journal of Physical Chemistry B 05/2014; 118(24). DOI:10.1021/jp503458w · 3.38 Impact Factor
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    ABSTRACT: The aggregation processes of amyloid-β-(16-22) peptides (Aβ16-22) are investigated by atomic force microscopy (AFM). It is found that Aβ16-22 peptides quickly aggregate from monomers to oligomers and flake-like structures, and finally to fibrils. In particular, unusual morphology change is observed at the early stage of aggregation, that is, the originally formed flake-like structures would disappear in the followed aggregation processes. To figure out the evolution of the flake-like structures, in-situ AFM imaging is carried out in liquid to reveal the real-time morphology changing of Aβ16-22. The results provide clear evidences that the flake-like structures are in unstable intermediate state, which would be dissolved into oligomers or short protofibrils for reorganization. Further experiments of Thioflavin T (ThT) fluorescence and attenuated total reflectance Fourier transform infrared (ATR-FTIR) suggest that those flake-like structures contain β-sheet components.
    Langmuir 03/2014; 30(11). DOI:10.1021/la4048165 · 4.38 Impact Factor
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    ABSTRACT: Seeded conversion of tau monomers into fibrils is a central step in the progression of tau pathology in Alzheimer's disease and other neurodegenerative disorders. Self-assembly is mediated by the microtubule binding repeats in tau. There are either three or four repeats present depending on the protein isoform. Here, double electron-electron resonance spectroscopy was used to investigate the conformational ensemble of four-repeat tau fibrils. Single point mutations at key positions in the protein (ΔK280, P301S, P312I, D314I) markedly change the distribution of fibril conformers after template-assisted growth, whereas other mutations in the protein (I308M, S320F, G323I, G326I, Q336R) do not. These findings provide unprecedented insights into the seed selection of tau disease mutants and establish conformational compatibility as an important driving force in tau fibril propagation.
    Angewandte Chemie International Edition 02/2014; 53(6). DOI:10.1002/anie.201308473 · 11.34 Impact Factor
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    ABSTRACT: Understanding the nature of the self-assembly of peptide nanostructures at the molecular level is critical for rational design of functional bio-nanomaterials. Recent experimental studies have shown that triphenylalanine(FFF)-based peptides can self-assemble into solid plate-like nanostructures and nanospheres, which are different from the hollow nanovesicles and nanotubes formed by diphenylalanine(FF)-based peptides. In spite of extensive studies, the assembly mechanism and the molecular basis for the structural differences between FFF and FF nanostructures remain poorly understood. In this work, we first investigate the assembly process and the structural features of FFF nanostructures using coarse-grained molecular dynamics simulations, and then compare them with FF nanostructures. We find that FFF peptides spontaneously assemble into solid nanometer-sized nanospheres and nanorods with substantial β-sheet contents, consistent with the structural properties of hundred-nanometer-sized FFF nano-plates characterized by FT-IR spectroscopy. Distinct from the formation mechanism of water-filled FF nanovesicles and nanotubes reported in our previous study, intermediate bilayers are not observed during the self-assembly process of FFF nanospheres and nanorods. The peptides in FFF nanostructures are predominantly anti-parallel-aligned, which can form larger sizes of β-sheet-like structures than the FF counterparts. In contrast, FF peptides exhibit lipid-like assembly behavior and assemble into bilayered nanostructures. Furthermore, although the self-assembly of FF and FFF peptides is mostly driven by side chain-side chain (SC-SC) aromatic stacking interactions, the main chain-main chain (MC-MC) interactions also play an important role in the formation of fine structures of the assemblies. The delicate interplay between MC-MC and SC-SC interactions results in the different nanostructures formed by the two peptides. These findings provide new insights into the structure and self-assembly pathway of di-/tri-phenylalanine peptide assemblies, which might be helpful for the design of bioinspired nanostructures.
    Nanoscale 01/2014; 6(5). DOI:10.1039/c3nr02505e · 6.74 Impact Factor
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    ABSTRACT: Experiments suggested that the fibrillation of the 11-25 fragment (hIAPP(11-25)) of human islet amyloid polypeptide (hIAPP or amylin) involves the formation of transient α-helical intermediates, followed by conversion to β-sheet-rich structure. However, atomic details of α-helical intermediates and the transition mechanism are mostly unknown. We investigated the structural properties of monomer and dimer in atomistic detail by replica exchange molecular dynamics (REMD) simulations. Transient α-helical monomers and dimers were both observed in the REMD trajectories. Our calculated H(α) chemical shifts based on monomer REMD run are in agreement with the solution-state NMR experimental observations. Multiple 300-ns MD simulations at 310 K show α-helix-to-β-sheet transition follows two mechanisms: the first involved direct transition of the random coil part of the helical conformation into antiparallel β-sheet; in the second, the α-helical conformation unfolded and converted into antiparallel β-sheet. In both mechanisms, α-helix-to-β-sheet transition occurred via random coil and the transition was accompanied by increase of inter-peptide contacts. In addition, our REMD simulations revealed different temperature dependencies of helical and β-structures. Comparison with experimental data suggests that the propensity for hIAPP(11-25) to form α-helices and amyloid structures is concentration- and temperature-dependent.
    Biomacromolecules 12/2013; 15(1). DOI:10.1021/bm401406e · 5.79 Impact Factor
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    ABSTRACT: Recent experimental study reported that termini-uncapped Aβ(16-22) (with sequence KLVFFAE) peptides self-assembled into nanofibrils at pH 2.0. The oligomerization of this uncapped peptide at atomic-level in acidic pH condition remains to be determined as computational studies mainly focus on the self-assembly of capped Aβ(16-22) peptides at neutral pH condition. In this study, using replica exchange molecular dynamics (REMD) simulations with explicit solvent, we investigated the octameric structures of the uncapped Aβ(16-22) and its F19W variant at acidic pH condition. Our simulations reveal that the Aβ(16-22) octamers adopt various conformations, including closed β-barrels, bilayer β-sheets, and disordered aggregates. The closed β-barrel conformation is particularly interesting as cylindrical β-barrel has been reported recently as a cytotoxic species. Inter-peptide contact probability analyses between all pairs of residues reveal that the hydrophobic and aromatic stacking interactions between Phe19 residues play an essential role in the formation of β-barrels and bilayer β-sheets. The importance of Phe19 and the steric effect on the structures of Aβ(16-22) octamers are further examined by REMD simulation of F19W mutant. This REMD run shows that substitution of Phe19 by Trp with a more bulky aromatic side chain significantly reduces the β-sheet content and in turn induces the formation of disordered aggregates, indicating that steric effect significantly affect the self-assembly of low molecular weight Aβ(16-22) oligomers.
    The Journal of Physical Chemistry B 08/2013; 117(35). DOI:10.1021/jp405869a · 3.38 Impact Factor
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    ABSTRACT: Recent experiments in function mechanism study reported that a pH low-insertion peptide (pHLIP) can insert into a zwitterionic palmitoyloleoylphosphatidylcholine (POPC) lipid bilayer at acidic pH while binding to the bilayer surface at basic pH. However, the atomic details of the pH-dependent interaction of pHLIP with a POPC bilayer are not well understood. In this study, we investigate the detailed interactions of pHLIP with a POPC bilayer at acidic and basic pH conditions as those used in function mechanism study, using all-atom molecular dynamics (MD) simulations. Simulations have been performed by employing the initial configurations, where pHLIP is placed in aqueous solution, parallel to bilayer surface (system S), partially-inserted (system P), or fully-inserted (system F) in POPC bilayers. On the basis of multiple 200-ns MD simulations, we found (1) pHLIP in system S can spontaneously insert into a POPC bilayer at acidic pH, while binding to the membrane surface at basic pH; (2) pHLIP in system P can insert deep into a POPC bilayer at acidic pH, while it has a tendency to exit, and stays at bilayer surface at basic pH; (3) pHLIP in system F keeps in an α-helical structure at acidic pH while partially unfolding at basic pH. This study provides at atomic-level the pH-induced insertion of pHLIP into POPC bilayer.
    International Journal of Molecular Sciences 07/2013; 14(7):14532-49. DOI:10.3390/ijms140714532 · 2.34 Impact Factor
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    ABSTRACT: We computationally and experimentally showed that tau protein fibrils can be formed at high temperature. When cooled, the fibrils dissociate back to monomers. Heparin promotes tau fibril formation and prevents its reversion. Our results revealed the physicochemical mechanism of reversible formation of tau fibrils.
    Chemical Communications 03/2013; DOI:10.1039/c3cc00241a · 6.72 Impact Factor
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    ABSTRACT: Homogeneous assemblies of the model peptides at interfaces have been achieved and observed with scanning tunneling microscopy. The dependence of the observed brightness in STM images is analyzed and the correlation with the peptide residues is proposed. We have also investigated the conformational dynamics of the peptide assemblies adsorbed on a graphene sheet by performing all-atom molecular dynamic simulations in water at 300 K. The simulation results of the two peptide assemblies on graphite surfaces show that R4G4H8 and F4G4H8 peptide assemblies are mostly in beta-sheet structure, and the interaction energy of the four different residues with graphite surfaces follows the order of Phe > His > Arg > Gly, consistent with their brightness contrasts in STM images. The insight on the distribution of residue moieties in the peptide assemblies could provide beneficial venues for studying peptide-based interfacial processes such as site-specific interactions between molecular species with peptides.
    Journal of the American Chemical Society 01/2013; 135(6). DOI:10.1021/ja307198u · 11.44 Impact Factor
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    ABSTRACT: The molecular structures and assembly structures of aromatic oligoamide macrocycles are identified by using scanning tunneling microscopy at liquid/solid interface, which shows persistent shapes, tunable cavity sizes, and binding of water molecules.
    ChemPhysChem 11/2012; 13(16). DOI:10.1002/cphc.201200288 · 3.36 Impact Factor
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    ABSTRACT: Interactions of human islet amyloid polypeptide (hIAPP or amylin) with the cell membrane are correlated with the dysfunction and death of pancreatic islet β-cells in type II diabetes. Formation of receptor-independent channels by hIAPP in the membrane is regarded as one of the membrane-damaging mechanisms that induce ion homeostasis and toxicity in islet β-cells. Here, we investigate the dynamic structure, ion conductivity, and membrane interactions of hIAPP channels in the DOPC bilayer using molecular modeling and molecular dynamics simulations. We use the NMR-derived β-strand-turn-β-strand motif as a building block to computationally construct a series of annular-like hIAPP structures with different sizes and topologies. In the simulated lipid environments, the channels lose their initial continuous β-sheet network and break into oligomeric subunits, which are still loosely associated to form heterogeneous channel conformations. The channels' shapes, morphologies and dimensions are compatible with the doughnut-like images obtained by atomic force microscopy, and with those of modeled channels for Aβ, the β(2)-microglobulin-derived K3 peptides, and the β-hairpin-based channels of antimicrobial peptide PG-1. Further, all channels induce directional permeability of multiple ions across the bilayers from the lower to the upper leaflet. This similarity suggests that loosely-associated β-structure motifs can be a general feature of toxic, unregulated channels. In the absence of experimental high-resolution atomic structures of hIAPP channels in the membrane, this study represents a first attempt to delineate some of the main structural features of the hIAPP channels, for a better understanding of the origin of amyloid toxicity and the development of pharmaceutical agents.
    Biochimica et Biophysica Acta 08/2012; 1818(12):3121-30. DOI:10.1016/j.bbamem.2012.08.012 · 4.66 Impact Factor
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    ABSTRACT: Tau pathology in Alzheimer's disease is intimately linked to the deposition of proteinacious filaments, which akin to infectious prions, have been proposed to spread via seeded conversion. Here we use double electron-electron resonance (DEER) spectroscopy in combination with extensive computational analysis to show that filaments of three- (3R) and four-repeat (4R) tau are conformationally distinct. Distance measurements between spin labels in the third repeat, reveal tau amyloid filaments as ensembles of known β-strand-turn-β-strand U-turn motifs. Whereas filaments seeded with 3R tau are structurally homogeneous, filaments seeded with 4R tau are heterogeneous, composed of at least three distinct conformers. These findings establish a molecular basis for the seeding barrier between different tau isoforms and offer a new powerful approach for investigating the composition and dynamics of amyloid fibril ensembles.
    Journal of the American Chemical Society 06/2012; 134(24):10271-8. DOI:10.1021/ja303498q · 11.44 Impact Factor
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    ABSTRACT: The aggregation of human islet amyloid polypeptide (hIAPP or amylin) is associated with the pathogenesis of type 2 diabetes mellitus. Increasing evidence suggests that the interaction of hIAPP with β-cell membranes plays a crucial role in cytotoxicity. However, the hIAPP-lipid interaction and subsequent membrane perturbation is not well understood at atomic level. In this study, as a first step to gain insight into the mechanism of hIAPP-induced cytotoxicity, we have investigated the detailed interactions of hIAPP monomer and dimer with anionic palmitoyloleolyophosphatidylglycerol (POPG) bilayer using all-atom molecular dynamics (MD) simulations. Multiple MD simulations have been performed by employing the initial configurations where the N-terminal region of hIAPP is pre-inserted in POPG bilayer. Our simulations show that electrostatic interaction between hIAPP and POPG bilayer plays a major role in peptide-lipid interaction. In particular, the N-terminal positively-charged residues Lys1 and Arg11 make a dominant contribution to the interaction. During peptide-lipid interaction process, peptide dimerization occurs mostly through the C-terminal 20-37 region containing the amyloidogenic 20-29-residue segment. Membrane-bound hIAPP dimers display a pronounced ability of membrane perturbation than monomers. The higher bilayer perturbation propensity of hIAPP dimer likely results from the cooperativity of the peptide-peptide interaction (or peptide aggregation). This study provides insight into the hIAPP-membrane interaction and the molecular mechanism of membrane disruption by hIAPP oligomers.
    PLoS ONE 05/2012; 7(5):e38191. DOI:10.1371/journal.pone.0038191 · 3.53 Impact Factor
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    ABSTRACT: Nanostructures, particularly those from peptide self-assemblies, have attracted great attention lately due to their potential applications in nanotemplating and nanotechnology. Recent experimental studies reported that diphenylalanine-based peptides can self-assemble into highly ordered nanostructures such as nanovesicles and nanotubes. However, the molecular mechanism of the self-organization of such well-defined nanoarchitectures remains elusive. In this study, we investigate the assembly pathway of 600 diphenylalanine (FF) peptides at different peptide concentrations by performing extensive coarse-grained molecular dynamics (MD) simulations. Based on forty 0.6-1.8 μs trajectories at 310 K starting from random configurations, we find that FF dipeptides not only spontaneously assemble into spherical vesicles and nanotubes, consistent with previous experiments, but also form new ordered nanoarchitectures, namely, planar bilayers and a rich variety of other shapes of vesicle-like structures including toroid, ellipsoid, discoid, and pot-shaped vesicles. The assembly pathways are concentration-dependent. At low peptide concentrations, the self-assembly involves the fusion of small vesicles and bilayers, whereas at high concentrations, it occurs through the formation of a bilayer first, followed by the bending and closure of the bilayer. Energetic analysis suggests that the formation of different nanostructures is a result of the delicate balance between peptide-peptide and peptide-water interactions. Our all-atom MD simulation shows that FF nanostructures are stabilized by a combination of T-shaped aromatic stacking, interpeptide head-to-tail hydrogen-bonding, and peptide-water hydrogen-bonding interactions. This study provides, for the first time to our knowledge, the self-assembly mechanism and the molecular organization of FF dipeptide nanostructures.
    ACS Nano 04/2012; 6(5):3907-18. DOI:10.1021/nn300015g · 12.03 Impact Factor
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    ABSTRACT: In Alzheimer's disease and frontotemporal dementias, the microtubule-associated protein Tau forms intracellular paired helical filaments. The filaments can form not only by the full-length human Tau protein, but also by the three repeated (K19) or four repeated (K18) Tau segments. However, of interest, experimentally, K19 can seed K18, but not vice versa. To obtain insight into the cross-seeding between K18 and K19 aggregates, here, K18 and K19 octamers with repeat 3 (R3) in U-shaped, L-shaped, and long straight line-shaped (SL-shape) conformations are assembled into different structures. The simulation results show that K18-8/K19-8 (K18 and K19 assemblies number 8) with R3 in an L shape and K18-9/K19-9 with R3 in an SL shape are highly populated and present the highest structural similarity among all simulated K18 and K19 octamers, suggesting that similar folding of K18/K19 may serve as structural core for the K18-K19 co-assembled heterogeneous filament. We demonstrate that formation of stable R2 and R3 conformations is the critical step for K18 aggregation, and R3 is critical for K19 fibrillization. The different core units in K18 and K19 may create a cross-seeding barrier for the K18 seed to trigger K19 fibril growth because R2 is not available for K19. Our study provides insights into cross-seeding involving heterogeneous structures. The polymorphic nature of protein aggregation could be magnified in the cross-seeding process. If the seeding conformations lead to too much divergence in the energy landscape, it could impede fibril formation. Such an effect could also contribute to the asymmetric barrier between K18 and K19.
    Journal of Biological Chemistry 03/2012; 287(18):14950-9. DOI:10.1074/jbc.M112.340794 · 4.60 Impact Factor
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    ABSTRACT: Alzheimer's disease is associated with the abnormal self-assembly of the amyloid-β (Aβ) peptide into toxic β-rich aggregates. Experimental studies have shown that hydrophobic nanoparticles retard Aβ fibrillation by slowing down the nucleation process; however, the effects of nanoparticles on Aβ oligomeric structures remain elusive. In this study, we investigate the conformations of Aβ(16-22) octamers in the absence and presence of a single-walled carbon nanotube (SWCNT) by performing extensive all-atom replica exchange molecular-dynamics simulations in explicit solvent. Our simulations starting from eight random chains demonstrate that the addition of SWCNT into Aβ(16-22) solution prevents β-sheet formation. Simulation starting from a prefibrillar β-sheet octamer shows that SWCNT destabilizes the β-sheet structure. A detailed analysis of the Aβ(16-22)/SWCNT/water interactions reveals that both the inhibition of β-sheet formation and the destabilization of prefibrillar β-sheets by SWCNT result from the same physical forces: hydrophobic and π-stacking interactions (with the latter playing a more important role). By analyzing the stacking patterns between the Phe aromatic rings and the SWCNT carbon rings, we find that short ring-centroid distances mostly favor parallel orientation, whereas large distances allow all other orientations to be populated. Overall, our computational study provides evidence that SWCNT is likely to inhibit Aβ(16-22) and full-length Aβ fibrillation.
    Biophysical Journal 11/2011; 101(9):2267-76. DOI:10.1016/j.bpj.2011.09.046 · 3.83 Impact Factor