245 research outputs found
Parallelization of Markov chain generation and its application to the multicanonical method
We develop a simple algorithm to parallelize generation processes of Markov
chains. In this algorithm, multiple Markov chains are generated in parallel and
jointed together to make a longer Markov chain. The joints between the
constituent Markov chains are processed using the detailed balance. We apply
the parallelization algorithm to multicanonical calculations of the
two-dimensional Ising model and demonstrate accurate estimation of
multicanonical weights.Comment: 15 pages, 5 figures, uses elsart.cl
Multi-Overlap Simulations for Transitions between Reference Configurations
We introduce a new procedure to construct weight factors, which flatten the
probability density of the overlap with respect to some pre-defined reference
configuration. This allows one to overcome free energy barriers in the overlap
variable. Subsequently, we generalize the approach to deal with the overlaps
with respect to two reference configurations so that transitions between them
are induced. We illustrate our approach by simulations of the brainpeptide
Met-enkephalin with the ECEPP/2 energy function using the global-energy-minimum
and the second lowest-energy states as reference configurations. The free
energy is obtained as functions of the dihedral and the root-mean-square
distances from these two configurations. The latter allows one to identify the
transition state and to estimate its associated free energy barrier.Comment: 12 pages, (RevTeX), 14 figures, Phys. Rev. E, submitte
Protein folding mediated by solvation: water expelling and formation of the hydrophobic core occurs after the structure collapse
The interplay between structure-search of the native structure and
desolvation in protein folding has been explored using a minimalist model.
These results support a folding mechanism where most of the structural
formation of the protein is achieved before water is expelled from the
hydrophobic core. This view integrates water expulsion effects into the funnel
energy landscape theory of protein folding. Comparisons to experimental results
are shown for the SH3 protein. After the folding transition, a near-native
intermediate with partially solvated hydrophobic core is found. This transition
is followed by a final step that cooperatively squeezes out water molecules
from the partially hydrated protein core.Comment: Proceedings of the National Academy of Science, 2002, Vol.99. 685-69
Secondary-Structure Design of Proteins by a Backbone Torsion Energy
We propose a new backbone-torsion-energy term in the force field for protein
systems. This torsion-energy term is represented by a double Fourier series in
two variables, the backbone dihedral angles phi and psi. It gives a natural
representation of the torsion energy in the Ramachandran space in the sense
that any two-dimensional energy surface periodic in both phi and psi can be
expanded by the double Fourier series. We can then easily control
secondary-structure-forming tendencies by modifying the torsion-energy surface.
For instance, we can increase/decrease the alpha-helix-forming-tendencies by
lowering/raising the torsion-energy surface in the alpha-helix region and
likewise increase/decrease the beta-sheet-forming tendencies by
lowering/raising the surface in the beta-sheet region in the Ramachandran
space. We applied our approach to AMBER parm94 and AMBER parm96 force fields
and demonstrated that our modifications of the torsion-energy terms resulted in
the expected changes of secondary-structure-forming-tendencies by performing
folding simulations of alpha-helical and beta-hairpin peptides.Comment: 13 pages, (Revtex4), 5 figure
Temperature dependence of ESR intensity for the nanoscale molecular magnet V15
The electron spin resonance (ESR) of nanoscale molecular magnet is studied. Since the Hamiltonian of has a large
Hilbert space and numerical calculations of the ESR signal evaluating the Kubo
formula with exact diagonalization method is difficult, we implement the
formula with the help of the random vector technique and the Chebyshev
polynominal expansion, which we name the double Chebyshev expansion method. We
calculate the temperature dependence of the ESR intensity of and
compare it with the data obtained in experiment. As another complementary
approach, we also implement the Kubo formula with the subspace iteration method
taking only important low-lying states into account. We study the ESR
absorption curve below by means of both methods. We find that side
peaks appear due to the Dzyaloshinsky-Moriya interaction and these peaks grows
as temperature decreases.Comment: 9 pages, 4 figures. To appear in J. Phys. Soc. Jpn. Supp
Computing Chemical Potential using the Phase Space Multi-histogram Method
We present a new simulation method to calculate the free energy and the
chemical potential of hard particle systems. The method relies on the
introduction of a parameter dependent potential to smoothly transform between
the hard particle system and the corresponding ideal gas. We applied the method
to study the phase transition behavior of monodispersed infinitely thin square
platelets. First, we equilibrated the square platelet system for different
reduced pressures with a usual isobaric Monte Carlo (MC) simulation and
obtained a reduced pressure-chemical potential plot. Then we introduce the
parametrized potential to interpolate the system between the ideal gas and the
hard particles. After selecting the potential, we performed isochoric MC runs,
ranging from the ideal gas to the hard particle limit. Through an iterative
procedure, we compute the free energy and the chemical potential of the square
platelet system by evaluating the volume of the phase space attributed to the
hard particles, and then we find the coexistence pressure of the system. Our
method provides an intuitive approach to investigate the phase transitions of
hard particle systems
Targeting BRAF in thyroid cancer
Activating mutations in the gene encoding BRAF are the most commonly identified oncogenic abnormalities in papillary thyroid cancer. In vitro and in vivo models have demonstrated that overexpression of activated BRAF induces malignant transformation and aggressive tumour behaviour. BRAF and other RAF kinases are frequently activated by other thyroid oncogenes and are important mediators of their biological effects including dedifferentiation and proliferation. Because current therapeutic options for patients with thyroid cancers that are aggressive and/or do not respond to standard therapies are limited, BRAF and its downstream effectors represent attractive therapeutic targets. In this review, data supporting a role for BRAF activation in thyroid cancer development and establishing the potential therapeutic efficacy of BRAF-targeted agents in patients with thyroid cancer will be reviewed
Enhanced and effective conformational sampling of protein molecular systems for their free energy landscapes
Protein folding and proteinβligand docking have long persisted as important subjects in biophysics. Using multicanonical molecular dynamics (McMD) simulations with realistic expressions, i.e., all-atom protein models and an explicit solvent, free-energy landscapes have been computed for several systems, such as the folding of peptides/proteins composed of a few amino acids up to nearly 60 amino-acid residues, proteinβligand interactions, and coupled folding and binding of intrinsically disordered proteins. Recent progress in conformational sampling and its applications to biophysical systems are reviewed in this report, including descriptions of several outstanding studies. In addition, an algorithm and detailed procedures used for multicanonical sampling are presented along with the methodology of adaptive umbrella sampling. Both methods control the simulation so that low-probability regions along a reaction coordinate are sampled frequently. The reaction coordinate is the potential energy for multicanonical sampling and is a structural identifier for adaptive umbrella sampling. One might imagine that this probability control invariably enhances conformational transitions among distinct stable states, but this study examines the enhanced conformational sampling of a simple system and shows that reasonably well-controlled sampling slows the transitions. This slowing is induced by a rapid change of entropy along the reaction coordinate. We then provide a recipe to speed up the sampling by loosening the rapid change of entropy. Finally, we report all-atom McMD simulation results of various biophysical systems in an explicit solvent
Copy Number Alteration and Uniparental Disomy Analysis Categorizes Japanese Papillary Thyroid Carcinomas into Distinct Groups
The aim of the present study was to investigate chromosomal aberrations in sporadic Japanese papillary thyroid carcinomas (PTCs), concomitant with the analysis of oncogene mutational status. Twenty-five PTCs (11 with BRAFV600E, 4 with RET/PTC1, and 10 without mutation in HRAS, KRAS, NRAS, BRAF, RET/PTC1, or RET/PTC3) were analyzed using Genome-Wide Human SNP Array 6.0 which allows us to detect copy number alteration (CNA) and uniparental disomy (UPD), also referred to as copy neutral loss of heterozygosity, in a single experiment. The Japanese PTCs showed relatively stable karyotypes. Seven cases (28%) showed CNA(s), and 6 (24%) showed UPD(s). Interestingly, CNA and UPD were rarely overlapped in the same tumor; the only one advanced case showed both CNA and UPD with a highly complex karyotype. Thirteen (52%) showed neither CNA nor UPD. Regarding CNA, deletions tended to be more frequent than amplifications. The most frequent and recurrent region was the deletion in chromosome 22; however, it was found in only 4 cases (16%). The degree of genomic instability did not depend on the oncogene status. However, in oncogene-positive cases (BRAFV600E and RET/PTC1), tumors with CNA/UPD were less frequent (5/15, 33%), whereas tumors with CNA/UPD were more frequent in oncogene-negative cases (7/10, 70%), suggesting that chromosomal aberrations may play a role in the development of PTC, especially in oncogene-negative tumors. These data suggest that Japanese PTCs may be classified into three distinct groups: CNA+, UPD+, and no chromosomal aberrations. BRAFV600E mutational status did not correlate with any parameters of chromosomal defects
Cross-Regulation between Oncogenic BRAFV600E Kinase and the MST1 Pathway in Papillary Thyroid Carcinoma
BACKGROUND:The BRAF(V600E) mutation leading to constitutive signaling of MEK-ERK pathways causes papillary thyroid cancer (PTC). Ras association domain family 1A (RASSF1A), which is an important regulator of MST1 tumor suppressor pathways, is inactivated by hypermethylation of its promoter region in 20 to 32% of PTC. However, in PTC without RASSF1A methylation, the regulatory mechanisms of RASSF1A-MST1 pathways remain to be elucidated, and the functional cooperation or cross regulation between BRAF(V600E) and MST1,which activates Foxo3,has not been investigated. METHODOLOGY/PRINCIPAL FINDINGS:The negative regulators of the cell cycle, p21 and p27, are strongly induced by transcriptional activation of FoxO3 in BRAF(V600E) positive thyroid cancer cells. The FoxO3 transactivation is augmented by RASSF1A and the MST1 signaling pathway. Interestingly, introduction of BRAF(V600E)markedly abolished FoxO3 transactivation and resulted in the suppression of p21 and p27 expression. The suppression of FoxO3 transactivation by BRAF(V600E)is strongly increased by coexpression of MST1 but it is not observed in the cells in which MST1, but not MST2,is silenced. Mechanistically, BRAF(V600E)was able to bind to the C-terminal region of MST1 and resulted in the suppression of MST1 kinase activities. The induction of the G1-checkpoint CDK inhibitors, p21 and p27,by the RASSF1A-MST1-FoxO3 pathway facilitates cellular apoptosis, whereas addition of BRAF(V600E) inhibits the apoptotic processes through the inactivation of MST1. Transgenic induction of BRAF(V600E)in the thyroid gland results in cancers resembling human papillary thyroid cancers. The development of BRAF(V600E)transgenic mice with the MST1 knockout background showed that these mice had abundant foci of poorly differentiated carcinomas and large areas without follicular architecture or colloid formation. CONCLUSIONS/SIGNIFICANCE:The results of this study revealed that the oncogenic effect of BRAF(V600E) is associated with the inhibition of MST1 tumor suppressor pathways, and that the activity of RASSF1A-MST1-FoxO3 pathways determines the phenotypes of BRAF(V600E) tumors
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