194 research outputs found
Role of electrostatic interactions in amyloid beta-protein (Abeta) oligomer formation: A discrete molecular dynamics study
Pathological folding and oligomer formation of the amyloid beta-protein
(Abeta) are widely perceived as central to Alzheimer's disease (AD).
Experimental approaches to study Abeta self-assembly are problematic, because
most relevant aggregates are quasi-stable and inhomogeneous. We apply a
discrete molecular dynamics (DMD) approach combined with a four-bead protein
model to study oligomer formation of the amyloid beta-protein (Abeta). We
address the differences between the two most common Abeta alloforms, Abeta40
and Abeta42, which oligomerize differently in vitro. We study how the presence
of electrostatic interactions (EIs) between pairs of charged amino acids
affects Abeta40 and Abeta42 oligomer formation. Our results indicate that EIs
promote formation of larger oligomers in both Abeta40 and Abeta42. The Abeta40
size distribution remains unimodal, whereas the Abeta42 distribution is
trimodal, as observed experimentally. Abeta42 folded structure is characterized
by a turn in the C-terminus that is not present in Abeta40. We show that the
same C-terminal region is also responsible for the strongest intermolecular
contacts in Abeta42 pentamers and larger oligomers. Our results suggest that
this C-terminal region plays a key role in the formation of Abeta42 oligomers
and the relative importance of this region increases in the presence of EIs.
These results suggest that inhibitors targeting the C-terminal region of
Abeta42 oligomers may be able to prevent oligomer formation or structurally
modify the assemblies to reduce their toxicity.Comment: Accepted for publication at Biophysical Journa
Automated identification of neurons and their locations
Individual locations of many neuronal cell bodies (>10^4) are needed to
enable statistically significant measurements of spatial organization within
the brain such as nearest-neighbor and microcolumnarity measurements. In this
paper, we introduce an Automated Neuron Recognition Algorithm (ANRA) which
obtains the (x,y) location of individual neurons within digitized images of
Nissl-stained, 30 micron thick, frozen sections of the cerebral cortex of the
Rhesus monkey. Identification of neurons within such Nissl-stained sections is
inherently difficult due to the variability in neuron staining, the overlap of
neurons, the presence of partial or damaged neurons at tissue surfaces, and the
presence of non-neuron objects, such as glial cells, blood vessels, and random
artifacts. To overcome these challenges and identify neurons, ANRA applies a
combination of image segmentation and machine learning. The steps involve
active contour segmentation to find outlines of potential neuron cell bodies
followed by artificial neural network training using the segmentation
properties (size, optical density, gyration, etc.) to distinguish between
neuron and non-neuron segmentations. ANRA positively identifies 86[5]% neurons
with 15[8]% error (mean[st.dev.]) on a wide range of Nissl-stained images,
whereas semi-automatic methods obtain 80[7]%/17[12]%. A further advantage of
ANRA is that it affords an unlimited increase in speed from semi-automatic
methods, and is computationally efficient, with the ability to recognize ~100
neurons per minute using a standard personal computer. ANRA is amenable to
analysis of huge photo-montages of Nissl-stained tissue, thereby opening the
door to fast, efficient and quantitative analysis of vast stores of archival
material that exist in laboratories and research collections around the world.Comment: 38 pages. Formatted for two-sided printing. Supplemental material and
software available at http://physics.bu.edu/~ainglis/ANRA
Molecular Dynamics Simulation of Amyloid Beta Dimer Formation
Recent experiments with amyloid-beta (Abeta) peptide suggest that formation
of toxic oligomers may be an important contribution to the onset of Alzheimer's
disease. The toxicity of Abeta oligomers depends on their structure, which is
governed by assembly dynamics. Due to limitations of current experimental
techniques, a detailed knowledge of oligomer structure at the atomic level is
missing. We introduce a molecular dynamics approach to study Abeta dimer
formation: (1) we use discrete molecular dynamics simulations of a
coarse-grained model to identify a variety of dimer conformations, and (2) we
employ all-atom molecular mechanics simulations to estimate the thermodynamic
stability of all dimer conformations. Our simulations of a coarse-grained Abeta
peptide model predicts ten different planar beta-strand dimer conformations. We
then estimate the free energies of all dimer conformations in all-atom
molecular mechanics simulations with explicit water. We compare the free
energies of Abeta(1-42) and Abeta(1-40) dimers. We find that (a) all dimer
conformations have higher free energies compared to their corresponding
monomeric states, and (b) the free energy difference between the Abeta(1-42)
and the analogous Abeta(1-40) dimer conformation is not significant. Our
results suggest that Abeta oligomerization is not accompanied by the formation
of stable planar beta-strand Abeta dimers.Comment: 32 pages (preprint format), 3 figure
Correlations in the Sine-Gordon Model with Finite Soliton Density
We study the sine-Gordon (SG) model at finite densities of the topological
charge and small SG interaction constant, related to the one-dimensional
Hubbard model near half-filling. Using the modified WKB approach, we find that
the spectrum of the Gaussian fluctuations around the classical solution
reproduces the results of the Bethe ansatz studies. The modification of the
collective coordinate method allows us to write down the action, free from
infra-red divergencies. The behaviour of the density-type correlation functions
is non-trivial and we demonstrate the existence of leading and sub-leading
asymptotes. A consistent definition of the charge-raising operator is
discussed. The superconducting-type correlations are shown to decrease slowly
at small soliton densities, while the spectral weight of right (left) moving
fermions is spread over neighboring "4k_F" harmonics.Comment: 12 pages, 3 eps figures, REVTEX; a discussion of fermions is adde
Fluctuations and correlations in sandpile models
We perform numerical simulations of the sandpile model for non-vanishing
driving fields and dissipation rates . Unlike simulations
performed in the slow driving limit, the unique time scale present in our
system allows us to measure unambiguously response and correlation functions.
We discuss the dynamic scaling of the model and show that
fluctuation-dissipation relations are not obeyed in this system.Comment: 5 pages, latex, 4 postscript figure
A Bethe lattice representation for sandpiles
Avalanches in sandpiles are represented throughout a process of percolation
in a Bethe lattice with a feedback mechanism. The results indicate that the
frequency spectrum and probability distribution of avalanches resemble more to
experimental results than other models using cellular automata simulations.
Apparent discrepancies between experiments are reconciled. Critical behavior is
here expressed troughout the critical properties of percolation phenomena.Comment: 5 pages, 4 figures, submitted for publicatio
Tilt order parameters, polarity and inversion phenomena in smectic liquid crystals
The order parameters for the phenomenological description of the smectic-{\it
A} to smectic-{\it C} phase transition are formulated on the basis of molecular
symmetry and structure. It is shown that, unless the long molecular axis is an
axis of two-fold or higher rotational symmetry, the ordering of the molecules
in the smectic-{\it C} phase gives rise to more than one tilt order parameter
and to one or more polar order parameters. The latter describe the indigenous
polarity of the smectic-{\it C} phase, which is not related to molecular
chirality but underlies the appearance of spontaneous polarisation in chiral
smectics. A phenomenological theory of the phase transition is formulated by
means of a Landau expansion in two tilt order parameters (primary and
secondary) and an indigenous polarity order parameter. The coupling among these
order parameters determines the possibility of sign inversions in the
temperature dependence of the spontaneous polarisation and of the helical pitch
observed experimentally for some chiral smectic-{\it } materials. The
molecular interpretation of the inversion phenomena is examined in the light of
the new formulation.Comment: 12 pages, 5 figures, RevTe
Dimer Formation Enhances Structural Differences between Amyloid β-Protein (1–40) and (1–42): An Explicit-Solvent Molecular Dynamics Study
Amyloid -protein (A) is central to the pathology of Alzheimer's disease. A 5% difference in the primary structure of the two predominant alloforms, A and A, results in distinct assembly pathways and toxicity properties. Discrete molecular dynamics (DMD) studies of A and A assembly resulted in alloform-specific oligomer size distributions consistent with experimental findings. Here, a large ensemble of DMD–derived A and A monomers and dimers was subjected to fully atomistic molecular dynamics (MD) simulations using the OPLS-AA force field combined with two water models, SPCE and TIP3P. The resulting all-atom conformations were slightly larger, less compact, had similar turn and lower -strand propensities than those predicted by DMD. Fully atomistic A and A monomers populated qualitatively similar free energy landscapes. In contrast, the free energy landscape of A dimers indicated a larger conformational variability in comparison to that of A dimers. A dimers were characterized by an increased flexibility in the N-terminal region D1-R5 and a larger solvent exposure of charged amino acids relative to A dimers. Of the three positively charged amino acids, R5 was the most and K16 the least involved in salt bridge formation. This result was independent of the water model, alloform, and assembly state. Overall, salt bridge propensities increased upon dimer formation. An exception was the salt bridge propensity of K28, which decreased upon formation of A dimers and was significantly lower than in A dimers. The potential relevance of the three positively charged amino acids in mediating the A oligomer toxicity is discussed in the light of available experimental data
Generic Mechanism of Emergence of Amyloid Protofilaments from Disordered Oligomeric aggregates
The presence of oligomeric aggregates, which is often observed during the
process of amyloid formation, has recently attracted much attention since it
has been associated with neurodegenerative conditions such as Alzheimer's and
Parkinson's diseases. We provide a description of a sequence-indepedent
mechanism by which polypeptide chains aggregate by forming metastable
oligomeric intermediate states prior to converting into fibrillar structures.
Our results illustrate how the formation of ordered arrays of hydrogen bonds
drives the formation of beta-sheets within the disordered oligomeric aggregates
that form early under the effect of hydrophobic forces. Initially individual
beta-sheets form with random orientations, which subsequently tend to align
into protofilaments as their lengths increases. Our results suggest that
amyloid aggregation represents an example of the Ostwald step rule of first
order phase transitions by showing that ordered cross-beta structures emerge
preferentially from disordered compact dynamical intermediate assemblies.Comment: 14 pages, 4 figure
Discrete molecular dynamics simulations of peptide aggregation
We study the aggregation of peptides using the discrete molecular dynamics
simulations. At temperatures above the alpha-helix melting temperature of a
single peptide, the model peptides aggregate into a multi-layer parallel
beta-sheet structure. This structure has an inter-strand distance of 0.48 nm
and an inter-sheet distance of 1.0 nm, which agree with experimental
observations. In this model, the hydrogen bond interactions give rise to the
inter-strand spacing in beta-sheets, while the Go interactions among side
chains make beta-strands parallel to each other and allow beta-sheets to pack
into layers. The aggregates also contain free edges which may allow for further
aggregation of model peptides to form elongated fibrils.Comment: 15 pages, 8 figure
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