524 research outputs found
Urinary and faecal N-methylhistamine concentrations do not serve as markers for mast cell activation or clinical disease activity in dogs with chronic enteropathies
This study sought to correlate faecal and urinary N-methylhistamine (NMH) concentrations with resting versus degranulated duodenal mast cell numbers in dogs with chronic enteropathies (CE), and investigate correlations between intestinal mast cell activation and clinical severity of disease as assessed by canine chronic enteropathy clinical activity index (CCECAI), and between urinary and faecal NMH concentrations, mast cell numbers, and histopathological scores. Twenty-eight dogs with CE were included. Duodenal biopsies were stained with haematoxylin and eosin (H&E), toluidine blue, and by immunohistochemical labelling for tryptase. Duodenal biopsies were assigned a histopathological severity score, and duodenal mast cell numbers were counted in five high-power fields after metachromatic and immunohistochemical staining. Faecal and urinary NMH concentrations were measured by gas chromatography–mass spectrometry
Thermodynamics of aggregation of two proteins
We investigate aggregation mechanism of two proteins in a thermodynamically
unambiguous manner by considering the finite size effect of free energy
landscape of HP lattice protein model. Multi-Self-Overlap-Ensemble Monte Carlo
method is used for numerical calculations. We find that a dimer can be formed
spontaneously as a thermodynamically stable state when the system is small
enough. It implies the possibility that the aggregation of proteins in a cell
is triggered when they are confined in a small region by, for example, being
surrounded by other macromolecules.We also find that the dimer exhibits a
transition between unstable state and metastable state in the infinite system.Comment: jpsj2.cls, 7 pages, 14 figures; misconfigurations of Fig.Nos.
correcte
Thermodynamic stability of folded proteins against mutations
By balancing the average energy gap with its typical change due to mutations
for protein-like heteropolymers with M residues, we show that native states are
unstable to mutations on a scale M* ~ (lambda/sigma_mu)^(1/zeta_s), where
lambda is the dispersion in the interaction free energies and sigma_mu their
typical change. Theoretical bounds and numerical estimates (based on complete
enumeration on four lattices) of the instability exponent zeta_s are given. Our
analysis suggests that a limiting size of single-domain proteins should exist,
and leads to the prediction that small proteins are insensitive to random
mutations.Comment: 5 pages, 3 figures, to be published in Physical Review Letter
Reply to Comment on "Criterion that Determines the Foldability of Proteins"
We point out that the correlation between folding times and in protein-like heteropolymer models where
and are the collapse and folding transition temperatures
was already established in 1993 before the other presumed equivalent criterion
(folding times correlating with alone) was suggested. We argue that the
folding times for these models show no useful correlation with the energy gap
even if restricted to the ensemble of compact structures as suggested by
Karplus and Shakhnovich (cond-mat/9606037).Comment: 6 pages, Latex, 2 Postscript figures. Plots explicitly showing the
lack of correlation between folding time and energy gap are adde
Entropic Barriers, Frustration and Order: Basic Ingredients in Protein Folding
We solve a model that takes into account entropic barriers, frustration, and
the organization of a protein-like molecule. For a chain of size , there is
an effective folding transition to an ordered structure. Without frustration,
this state is reached in a time that scales as , with
. This scaling is limited by the amount of frustration which
leads to the dynamical selectivity of proteins: foldable proteins are limited
to monomers; and they are stable in {\it one} range of temperatures,
independent of size and structure. These predictions explain generic properties
of {\it in vivo} proteins.Comment: 4 pages, 4 Figures appended as postscript fil
Simple models of protein folding and of non--conventional drug design
While all the information required for the folding of a protein is contained
in its amino acid sequence, one has not yet learned how to extract this
information to predict the three--dimensional, biologically active, native
conformation of a protein whose sequence is known. Using insight obtained from
simple model simulations of the folding of proteins, in particular of the fact
that this phenomenon is essentially controlled by conserved (native) contacts
among (few) strongly interacting ("hot"), as a rule hydrophobic, amino acids,
which also stabilize local elementary structures (LES, hidden, incipient
secondary structures like --helices and --sheets) formed early
in the folding process and leading to the postcritical folding nucleus (i.e.,
the minimum set of native contacts which bring the system pass beyond the
highest free--energy barrier found in the whole folding process) it is possible
to work out a succesful strategy for reading the native structure of designed
proteins from the knowledge of only their amino acid sequence and of the
contact energies among the amino acids. Because LES have undergone millions of
years of evolution to selectively dock to their complementary structures, small
peptides made out of the same amino acids as the LES are expected to
selectively attach to the newly expressed (unfolded) protein and inhibit its
folding, or to the native (fluctuating) native conformation and denaturate it.
These peptides, or their mimetic molecules, can thus be used as effective
non--conventional drugs to those already existing (and directed at neutralizing
the active site of enzymes), displaying the advantage of not suffering from the
uprise of resistance
Protein structures and optimal folding emerging from a geometrical variational principle
Novel numerical techniques, validated by an analysis of barnase and
chymotrypsin inhibitor, are used to elucidate the paramount role played by the
geometry of the protein backbone in steering the folding to the correct native
state. It is found that, irrespective of the sequence, the native state of a
protein has exceedingly large number of conformations with a given amount of
structural overlap compared to other compact artificial backbones; moreover the
conformational entropies of unrelated proteins of the same length are nearly
equal at any given stage of folding. These results are suggestive of an
extremality principle underlying protein evolution, which, in turn, is shown to
be associated with the emergence of secondary structures.Comment: Revtex, 5 pages, 5 postscript figure
Geometric and Statistical Properties of the Mean-Field HP Model, the LS Model and Real Protein Sequences
Lattice models, for their coarse-grained nature, are best suited for the
study of the ``designability problem'', the phenomenon in which most of the
about 16,000 proteins of known structure have their native conformations
concentrated in a relatively small number of about 500 topological classes of
conformations. Here it is shown that on a lattice the most highly designable
simulated protein structures are those that have the largest number of
surface-core switchbacks. A combination of physical, mathematical and
biological reasons that causes the phenomenon is given. By comparing the most
foldable model peptides with protein sequences in the Protein Data Bank, it is
shown that whereas different models may yield similar designabilities,
predicted foldable peptides will simulate natural proteins only when the model
incorporates the correct physics and biology, in this case if the main folding
force arises from the differing hydrophobicity of the residues, but does not
originate, say, from the steric hindrance effect caused by the differing sizes
of the residues.Comment: 12 pages, 10 figure
Mean-Field HP Model, Designability and Alpha-Helices in Protein Structures
Analysis of the geometric properties of a mean-field HP model on a square
lattice for protein structure shows that structures with large number of switch
backs between surface and core sites are chosen favorably by peptides as unique
ground states. Global comparison of model (binary) peptide sequences with
concatenated (binary) protein sequences listed in the Protein Data Bank and the
Dali Domain Dictionary indicates that the highest correlation occurs between
model peptides choosing the favored structures and those portions of protein
sequences containing alpha-helices.Comment: 4 pages, 2 figure
A hybrid approach to protein folding problem integrating constraint programming with local search
<p>Abstract</p> <p>Background</p> <p>The protein folding problem remains one of the most challenging open problems in computational biology. Simplified models in terms of lattice structure and energy function have been proposed to ease the computational hardness of this optimization problem. Heuristic search algorithms and constraint programming are two common techniques to approach this problem. The present study introduces a novel hybrid approach to simulate the protein folding problem using constraint programming technique integrated within local search.</p> <p>Results</p> <p>Using the face-centered-cubic lattice model and 20 amino acid pairwise interactions energy function for the protein folding problem, a constraint programming technique has been applied to generate the neighbourhood conformations that are to be used in generic local search procedure. Experiments have been conducted for a few small and medium sized proteins. Results have been compared with both pure constraint programming approach and local search using well-established local move set. Substantial improvements have been observed in terms of final energy values within acceptable runtime using the hybrid approach.</p> <p>Conclusion</p> <p>Constraint programming approaches usually provide optimal results but become slow as the problem size grows. Local search approaches are usually faster but do not guarantee optimal solutions and tend to stuck in local minima. The encouraging results obtained on the small proteins show that these two approaches can be combined efficiently to obtain better quality solutions within acceptable time. It also encourages future researchers on adopting hybrid techniques to solve other hard optimization problems.</p
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