320 research outputs found
Mean first passage time analysis reveals rate-limiting steps, parallel pathways and dead ends in a simple model of protein folding
We have analyzed dynamics on the complex free energy landscape of protein
folding in the FOLD-X model, by calculating for each state of the system the
mean first passage time to the folded state. The resulting kinetic map of the
folding process shows that it proceeds in jumps between well-defined, local
free energy minima. Closer analysis of the different local minima allows us to
reveal secondary, parallel pathways as well as dead ends.Comment: 7 page
Expression of PAFR as Part of a Prosurvival Response to Chemotherapy: A Novel Target for Combination Therapy in Melanoma
Melanoma cells express the platelet-activating factor receptor (PAFR) and, thus, respond to PAF, a bioactive lipid produced by both tumour cells and those in the tumour microenvironment such as macrophages. Here, we show that treatment of a human melanoma SKmel37 cell line with cisplatin led to increased expression of PAFR and its accumulation. In the presence of exogenous PAF, melanoma cells were significantly more resistant to cisplatin-induced cell death. Inhibition of PAFR-dependent signalling pathways by a PAFR antagonist (WEB2086) showed chemosensitisation of melanoma cells in vitro. Nude mice were inoculated with SKmel37 cells and treated with cisplatin and WEB2086. Animals treated with both agents showed significantly decreased tumour growth compared to the control group and groups treated with only one agent. PAFR accumulation and signalling are part of a prosurvival program of melanoma cells, therefore constituting a promising target for combination therapy for melanomas
Expression of PAFR as Part of a Prosurvival Response to Chemotherapy: A Novel Target for Combination Therapy in Melanoma
Melanoma cells express the platelet-activating factor receptor (PAFR) and, thus, respond to PAF, a bioactive lipid produced by both tumour cells and those in the tumour microenvironment such as macrophages. Here, we show that treatment of a human melanoma SKmel37 cell line with cisplatin led to increased expression of PAFR and its accumulation. In the presence of exogenous PAF, melanoma cells were significantly more resistant to cisplatin-induced cell death. Inhibition of PAFR-dependent signalling pathways by a PAFR antagonist (WEB2086) showed chemosensitisation of melanoma cells in vitro. Nude mice were inoculated with SKmel37 cells and treated with cisplatin and WEB2086. Animals treated with both agents showed significantly decreased tumour growth compared to the control group and groups treated with only one agent. PAFR accumulation and signalling are part of a prosurvival program of melanoma cells, therefore constituting a promising target for combination therapy for melanomas
Large phenotype jumps in biomolecular evolution
By defining the phenotype of a biopolymer by its active three-dimensional
shape, and its genotype by its primary sequence, we propose a model that
predicts and characterizes the statistical distribution of a population of
biopolymers with a specific phenotype, that originated from a given genotypic
sequence by a single mutational event. Depending on the ratio g0 that
characterizes the spread of potential energies of the mutated population with
respect to temperature, three different statistical regimes have been
identified. We suggest that biopolymers found in nature are in a critical
regime with g0 in the range 1-6, corresponding to a broad, but not too broad,
phenotypic distribution resembling a truncated Levy flight. Thus the biopolymer
phenotype can be considerably modified in just a few mutations. The proposed
model is in good agreement with the experimental distribution of activities
determined for a population of single mutants of a group I ribozyme.Comment: to appear in Phys. Rev. E; 7 pages, 6 figures; longer discussion in
VII, new fig.
Folding, Design and Determination of Interaction Potentials Using Off-Lattice Dynamics of Model Heteropolymers
We present the results of a self-consistent, unified molecular dynamics study
of simple model heteropolymers in the continuum with emphasis on folding,
sequence design and the determination of the interaction parameters of the
effective potential between the amino acids from the knowledge of the native
states of the designed sequences.Comment: 8 pages, 3 Postscript figures, uses RevTeX. Submitted to Physical
Review Letter
On the statistical mechanics of prion diseases
We simulate a two-dimensional, lattice based, protein-level statistical
mechanical model for prion diseases (e.g., Mad Cow disease) with concommitant
prion protein misfolding and aggregation. Our simulations lead us to the
hypothesis that the observed broad incubation time distribution in
epidemiological data reflect fluctuation dominated growth seeded by a few
nanometer scale aggregates, while much narrower incubation time distributions
for innoculated lab animals arise from statistical self averaging. We model
`species barriers' to prion infection and assess a related treatment protocol.Comment: 5 Pages, 3 eps figures (submitted to Physical Review Letters
Steric constraints in model proteins
A simple lattice model for proteins that allows for distinct sizes of the
amino acids is presented. The model is found to lead to a significant number of
conformations that are the unique ground state of one or more sequences or
encodable. Furthermore, several of the encodable structures are highly
designable and are the non-degenerate ground state of several sequences. Even
though the native state conformations are typically compact, not all compact
conformations are encodable. The incorporation of the hydrophobic and polar
nature of amino acids further enhances the attractive features of the model.Comment: RevTex, 5 pages, 3 postscript figure
Statistical mechanics of secondary structures formed by random RNA sequences
The formation of secondary structures by a random RNA sequence is studied as
a model system for the sequence-structure problem omnipresent in biopolymers.
Several toy energy models are introduced to allow detailed analytical and
numerical studies. First, a two-replica calculation is performed. By mapping
the two-replica problem to the denaturation of a single homogeneous RNA in
6-dimensional embedding space, we show that sequence disorder is perturbatively
irrelevant, i.e., an RNA molecule with weak sequence disorder is in a molten
phase where many secondary structures with comparable total energy coexist. A
numerical study of various models at high temperature reproduces behaviors
characteristic of the molten phase. On the other hand, a scaling argument based
on the extremal statistics of rare regions can be constructed to show that the
low temperature phase is unstable to sequence disorder. We performed a detailed
numerical study of the low temperature phase using the droplet theory as a
guide, and characterized the statistics of large-scale, low-energy excitations
of the secondary structures from the ground state structure. We find the
excitation energy to grow very slowly (i.e., logarithmically) with the length
scale of the excitation, suggesting the existence of a marginal glass phase.
The transition between the low temperature glass phase and the high temperature
molten phase is also characterized numerically. It is revealed by a change in
the coefficient of the logarithmic excitation energy, from being disorder
dominated to entropy dominated.Comment: 24 pages, 16 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
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