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Amyloid formation: interface influence
The causes of pathological conditions
such as Alzheimer’s and Parkinson’s
diseases are becoming better
understood. Proteins that misfold from
their native structure to form aggregates
of β-sheet fibrils — termed amyloid — are
known1,2 to be implicated in these ‘amyloid
diseases’. Understanding the early steps
of fibril formation is critical, and the
conditions, mechanism and kinetics of
protein and peptide aggregation are being
widely investigated through a variety of
in vitro studies.
Kinetic aspects of the dispersion of the
protein or peptide in solution are thought
to influence the fibrillization process by
mass-transfer effects. In addition, mixing also
leads to shear forces, which can influence
fibril growth by perturbing the equilibrium
between the isolated and aggregated proteins,
causing existing fibrils to fragment and create
new nuclei3. Writing in the Journal of the
American Chemical Society, David Talaga
and co-workers have now highlighted4 an
additional factor that can influence the
fibrillization of amyloid-forming proteins —
the presence of hydrophobic interfaces
The Effect of Nanoparticles on Amyloid Aggregation Depends on the Protein Stability and Intrinsic Aggregation Rate
Nanoparticles interfere with protein amyloid formation. Catalysis of the process may occur due to increased local protein concentration and nucleation on the nanoparticle surface, whereas tight binding or a large particle/protein surface area may lead to inhibition of protein aggregation. Here we show a clear correlation between the intrinsic protein stability and the nanoparticle effect on the aggregation rate. The results were reached for a series of five mutants of single-chain monellin differing in intrinsic stability toward denaturation, for which a correlation between protein stability and aggregation propensity has been previously documented by Szczepankiewicz et al. [Mol. Biosyst 2010 7 (2), 521-532]. The aggregation process was monitored by thioflavin T fluorescence in the absence and presence of copolyrneric nanoparticles with different hydrophobic characters. For mutants with a high intrinsic stability and low intrinsic aggregation rate, we find that amyloid fibril formation is accelerated by nanoparticles. For find the opposite-a retardation of amyloid fibril formation by nanoparticles. Moreover, both catalytic and inhibitory effects are most pronounced with the least hydrophobic nanoparticles, which have a larger surface accessibility of hydrogen-bonding groups in the polymer backbone
A superfluid hydrodynamic model for the enhanced moments of inertia of molecules in liquid 4He
We present a superfluid hydrodynamic model for the increase in moment of
inertia, , of molecules rotating in liquid He. The static
inhomogeneous He density around each molecule (calculated using the Orsay-Paris
liquid He density functional) is assumed to adiabatically follow the
rotation of the molecule. We find that the values created by the
viscousless and irrotational flow are in good agreement with the observed
increases for several molecules [ OCS, (HCN), HCCCN, and HCCCH ]. For
HCN and HCCH, our model substantially overestimates . This is likely
to result from a (partial) breakdown of the adiabatic following approximation.Comment: 4 pages, 1 eps figure, corrected version of published paper. Erratum
has been submitted for change
In Silico Theoretical Molecular Modeling for Alzheimer’s Disease: The Nicotine-Curcumin Paradigm in Neuroprotection and Neurotherapy
The aggregation of the amyloid-β-peptide (AβP) into well-ordered fibrils has been considered as the key pathological marker of Alzheimer‘s disease. Molecular attributes related to the specific binding interactions, covalently and non-covalently, of a library of compounds targeting of conformational scaffolds were computed employing static lattice atomistic simulations and array constructions. A combinatorial approach using isobolographic analysis was stochastically modeled employing Artificial Neural Networks and a Design of Experiments approach, namely an orthogonal Face-Centered Central Composite Design for small molecules, such as curcumin and glycosylated nornicotine exhibiting concentration-dependent behavior on modulating AβP aggregation and oligomerization. This work provides a mathematical and in silico approach that constitutes a new frontier in providing neuroscientists with a template for in vitro and in vivo experimentation. In future this could potentially allow neuroscientists to adopt this in silico approach for the development of novel therapeutic interventions in the neuroprotection and neurotherapy of Alzheimer‘s disease. In addition, the neuroprotective entities identified in this study may also be valuable in this regard
A Condensation-Ordering Mechanism in Nanoparticle-Catalyzed Peptide Aggregation
Nanoparticles introduced in living cells are capable of strongly promoting
the aggregation of peptides and proteins. We use here molecular dynamics
simulations to characterise in detail the process by which nanoparticle
surfaces catalyse the self- assembly of peptides into fibrillar structures. The
simulation of a system of hundreds of peptides over the millisecond timescale
enables us to show that the mechanism of aggregation involves a first phase in
which small structurally disordered oligomers assemble onto the nanoparticle
and a second phase in which they evolve into highly ordered beta-sheets as
their size increases
Dimensionality of Carbon Nanomaterials Determines the Binding and Dynamics of Amyloidogenic Peptides: Multiscale Theoretical Simulations
Experimental studies have demonstrated that nanoparticles can affect the rate of protein self-assembly, possibly interfering with the development of protein misfolding diseases such as Alzheimer's, Parkinson's and prion disease caused by aggregation and fibril formation of amyloid-prone proteins. We employ classical molecular dynamics simulations and large-scale density functional theory calculations to investigate the effects of nanomaterials on the structure, dynamics and binding of an amyloidogenic peptide apoC-II(60-70). We show that the binding affinity of this peptide to carbonaceous nanomaterials such as C60, nanotubes and graphene decreases with increasing nanoparticle curvature. Strong binding is facilitated by the large contact area available for π-stacking between the aromatic residues of the peptide and the extended surfaces of graphene and the nanotube. The highly curved fullerene surface exhibits reduced efficiency for π-stacking but promotes increased peptide dynamics. We postulate that the increase in conformational dynamics of the amyloid peptide can be unfavorable for the formation of fibril competent structures. In contrast, extended fibril forming peptide conformations are promoted by the nanotube and graphene surfaces which can provide a template for fibril-growth
Lipid vesicles trigger α-synuclein aggregation by stimulating primary nucleation.
α-Synuclein (α-syn) is a 140-residue intrinsically disordered protein that is involved in neuronal and synaptic vesicle plasticity, but its aggregation to form amyloid fibrils is the hallmark of Parkinson's disease (PD). The interaction between α-syn and lipid surfaces is believed to be a key feature for mediation of its normal function, but under other circumstances it is able to modulate amyloid fibril formation. Using a combination of experimental and theoretical approaches, we identify the mechanism through which facile aggregation of α-syn is induced under conditions where it binds a lipid bilayer, and we show that the rate of primary nucleation can be enhanced by three orders of magnitude or more under such conditions. These results reveal the key role that membrane interactions can have in triggering conversion of α-syn from its soluble state to the aggregated state that is associated with neurodegeneration and to its associated disease states.This work was supported by the UK BBSRC and the Wellcome Trust (CMD, TPJK, MV), the
Frances and Augustus Newman Foundation (TPJK), Magdalene College, Cambridge (AKB) , St John’s College,
Cambridge (TCTM), the Cambridge Home and EU Scholarship Scheme (GM), Elan Pharmaceuticals
(CMD, TPJK, MV, CG) and the Leverhulme Trust (AKB).This is the accepted manuscript. The final version is available from NPG at http://www.nature.com/nchembio/journal/v11/n3/abs/nchembio.1750.htm
Influence of gold nanoparticle surface chemistry and diameter upon Alzheimer’s disease amyloid-β protein aggregation
A simple model for metal cation-phosphate interactions in nucleic acids in the gas phase: Alkali metal cations and trimethyl phosphate
Kinetics of hydrolysis of 4-methoxyphenyl-2,2-dichloroethanoate in binary water-cosolvent mixtures; the role of solvent activity and solute-solute interactions
Rate constants are reported for the pH-independent hydrolysis of 4-methoxyphenyl-2,2-dichloroethanoate in aqueous solution as a function of the concentration of added cyanomethane ( acetonitrile), polyethylene glycol ( PEG 400) and tetrahydrofuran ( THF). The concentration of water was varied between ca. 25 and 55.5 M. It was found that the variation in water activity yields only a minor contribution to the observed variation in rate constants. Interestingly, for both cyanomethane and PEG 400 log(k) varies approximately linearly with the molar concentration of water. Medium effects in highly aqueous solutions ( [ H2O] > 50 M) of ethanol, 1-propanol, 2-propanol, 1-butanol and 2-methyl-2-propanol have also been determined. Unexpectedly, in this concentration range the alcohols induce significantly smaller effects per unit volume than cyanomethane. The present results are discussed in terms of pairwise interaction parameters. Isobaric activation parameters have been determined and reveal remarkable differences in the nature of the induced medium effects
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