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21.
Abstract The rotation diffusion of DNA double helices and their complexes with the cAMP receptor protein (CRP) has been simulated by bead models, in order to derive information on their structure in solution by comparison with results obtained from dichroism decay measurements. Straight DNA double helices are simulated by linear, rigid strings of overlapping beads. The radius of the beads and the length of the string are increased simultaneously by the same increments from initial outer dimensions derived from crystallographic data to final values, which are fitted to experimental rotation time constants observed for short DNA fragments (< 100 bp). The final values reflect the solvated structure with the same ‘solvation layer’ added in all three dimensions. The protein is simulated by overlapping beads, which are assembled to a structure very similar to that found by x-ray crystallography. Complexes of the protein with DNA are formed with the centres of palindromic DNA sites at the centre of the two helix- turn-helix-motifs of the protein with some overlap of the two components. Simulation of the experimental data obtained for CRP complexes with specific DNA in the presence of cAMP requires strong bending of the double helices. According to our simulation the DNA is almost completely wrapped around the protein both in the complexes with a 62 bp fragment containing the standard CRP site and with a 80 bp fragment containing the second binding site of the lac operon. Simulations of the data obtained for a 203 bp fragment with both binding sites suggest that the two bound CRP proteins are in contact with each other and that the DNA is wrapped around the two protein dimers. A stereochemical model is suggested with a tetrahedral arrangement of the four protein subunits, which provides the advantage that two binding sites of the protein formed by two subunits each are located favorable for tight contacts to two binding sites on bent DNA provided that the DNA sites are separated by an integer number of helix turns. In summary, the simulations demonstrate strong bending, which can be reflected by an arc radius in the range around 50 Å. According to these data the overall bending angle of our longest DNA fragment is approximately 180°, and thus the protruding ends are sufficiently close to each other such that RNA polymerase, for example, could contact both helical segments. 相似文献
22.
The electrostatic steering of charged ligands toward the active site of Torpedo californica acetylcholinesterase is investigated by Brownian dynamics simulations of wild type enzyme and several mutated forms, in which some normally charged residues are neutralized. The simulations reveal that the total ligand influx through a surface of 42 Å radius centered in the enzyme monomer and separated from the protein surface by I-14 Å is not significantly influenced by electrostatic interactions. Electrostatic effects are visible for encounters with a surface of 32 Å radius, which is partially hidden inside the protein, but mostly within the solvent. A clear accumulation of encounter events for that sphere is observed in the area directly above the entrance to the active site gorge. In this area, the encounter events are increased by 40% compared to the case of a neutral ligand. However, the differences among the encounter rates for the various mutants considered here are not pronounced, all rate constants being within ±10% of the average value. The enzyme charge distribution becomes more important as the charged ligand moves toward the bottom of the gorge, where the active site is located. We show that neither the enzyme's total charge, nor its dipole moment, fully account for the electrostatic steering of ligand to the active site. Higher moments of the enzyme's charge distribution are also important. However, for a series of mutations for which the direction of the enzyme dipole moment is constant within a few degrees, one observes a gradual decrease in the diffusional encounter rate constant with the number of neutralized residues. On the other hand, for other mutants that change the direction of the dipole moment from that of the wild type, the calculated encounter rate constants can be very close to that of the wild type. The present work yields two new insights to the kinetics of acetylcholinesterase. First, evolution appears to have built a redundant electrostatic steering capability into this important enzyme through the overall distribution of its thousands of partially charged atoms. And second, roughly half of the rate enhancement due to electrostatics arises from steering of the substrate outside the enzyme; the other half of the rate enhancement arises from improved trapping of the substrate after it has entered the gorge. The computational results reproduce qualitatively, and help to rationalize, many surprising experimental results obtained recently for human acetylcholinesterase. © 1996 John Wiley & Sons, Inc. 相似文献
23.
VLJ Whitehall TD Dumenil DM McKeone CE Bond ML Bettington RL Buttenshaw L Bowdler GW Montgomery LF Wockner BA Leggett 《Epigenetics》2014,9(11):1454-1460
The CpG Island Methylator Phenotype (CIMP) is fundamental to an important subset of colorectal cancer; however, its cause is unknown. CIMP is associated with microsatellite instability but is also found in BRAF mutant microsatellite stable cancers that are associated with poor prognosis. The isocitrate dehydrogenase 1 (IDH1) gene causes CIMP in glioma due to an activating mutation that produces the 2-hydroxyglutarate oncometabolite. We therefore examined IDH1 alteration as a potential cause of CIMP in colorectal cancer. The IDH1 mutational hotspot was screened in 86 CIMP-positive and 80 CIMP-negative cancers. The entire coding sequence was examined in 81 CIMP-positive colorectal cancers. Forty-seven cancers varying by CIMP-status and IDH1 mutation status were examined using Illumina 450K DNA methylation microarrays. The R132C IDH1 mutation was detected in 4/166 cancers. All IDH1 mutations were in CIMP cancers that were BRAF mutant and microsatellite stable (4/45, 8.9%). Unsupervised hierarchical cluster analysis identified an IDH1 mutation-like methylation signature in approximately half of the CIMP-positive cancers. IDH1 mutation appears to cause CIMP in a small proportion of BRAF mutant, microsatellite stable colorectal cancers. This study provides a precedent that a single gene mutation may cause CIMP in colorectal cancer, and that this will be associated with a specific epigenetic signature and clinicopathological features. 相似文献
24.
Jack?A?TuszynskiEmail author Philip?Winter Diana?White Chih-Yuan?Tseng Kamlesh?K?Sahu Francesco?Gentile Ivana?Spasevska Sara?Ibrahim?Omar Niloofar?Nayebi Cassandra?DM?Churchill Mariusz?Klobukowski Rabab?M?Abou?El-Magd 《Theoretical biology & medical modelling》2014,11(1):52
A variety of topics are reviewed in the area of mathematical and computational modeling in biology, covering the range of scales from populations of organisms to electrons in atoms. The use of maximum entropy as an inference tool in the fields of biology and drug discovery is discussed. Mathematical and computational methods and models in the areas of epidemiology, cell physiology and cancer are surveyed. The technique of molecular dynamics is covered, with special attention to force fields for protein simulations and methods for the calculation of solvation free energies. The utility of quantum mechanical methods in biophysical and biochemical modeling is explored. The field of computational enzymology is examined. 相似文献
25.
Background
The diversity of parasites attacking a host varies substantially among different host species. Understanding the factors that explain these patterns of parasite diversity is critical to identifying the ecological principles underlying biodiversity. Seabirds (Charadriiformes, Pelecaniformes and Procellariiformes) and their ectoparasitic lice (Insecta: Phthiraptera) are ideal model groups in which to study correlates of parasite species richness. We evaluated the relative importance of morphological (body size, body weight, wingspan, bill length), life-history (longevity, clutch size), ecological (population size, geographical range) and behavioural (diving versus non-diving) variables as predictors of louse diversity on 413 seabird hosts species. Diversity was measured at the level of louse suborder, genus, and species, and uneven sampling of hosts was controlled for using literature citations as a proxy for sampling effort. 相似文献26.
27.
J Antosiewicz 《Biophysical journal》1995,69(4):1344-1354
A simple and computationally feasible procedure for the calculation of net charges and dipole moments of proteins at arbitrary pH and salt conditions is described. The method is intended to provide data that may be compared to the results of transient electric dichroism experiments on protein solutions. The procedure consists of three major steps: (i) calculation of self energies and interaction energies for ionizable groups in the protein by using the finite-difference Poisson-Boltzmann method, (ii) determination of the position of the center of diffusion (to which the calculated dipole moment refers) and the extinction coefficient tensor for the protein, and (iii) generation of the equilibrium distribution of protonation states of the protein by a Monte Carlo procedure, from which mean and root-mean-square dipole moments and optical anisotropies are calculated. The procedure is applied to 12 proteins. It is shown that it gives hydrodynamic and electrical parameters for proteins in good agreement with experimental data. 相似文献
28.
David Ochoa Mindaugas Jonikas Robert T Lawrence Bachir El Debs Joel Selkrig Athanasios Typas Judit Villén Silvia DM Santos Pedro Beltrao 《Molecular systems biology》2016,12(12)
The coordinated regulation of protein kinases is a rapid mechanism that integrates diverse cues and swiftly determines appropriate cellular responses. However, our understanding of cellular decision‐making has been limited by the small number of simultaneously monitored phospho‐regulatory events. Here, we have estimated changes in activity in 215 human kinases in 399 conditions derived from a large compilation of phosphopeptide quantifications. This atlas identifies commonly regulated kinases as those that are central in the signaling network and defines the logic relationships between kinase pairs. Co‐regulation along the conditions predicts kinase–complex and kinase–substrate associations. Additionally, the kinase regulation profile acts as a molecular fingerprint to identify related and opposing signaling states. Using this atlas, we identified essential mediators of stem cell differentiation, modulators of Salmonella infection, and new targets of AKT1. This provides a global view of human phosphorylation‐based signaling and the necessary context to better understand kinase‐driven decision‐making. 相似文献
29.
Structure of the Tet repressor and Tet repressor-operator complexes in solution from electrooptical measurements and hydrodynamic simulations 总被引:3,自引:0,他引:3
The Tet repressor protein and tet operator DNA fragments and their complexes have been analyzed by electrooptical procedures. The protein shows a positive linear dichroism at 280 nm, a negative linear dichroism at 248 nm, and a strong permanent dipole moment of 3.5 X 10(-27) C m, which is independent of the salt concentration within experimental accuracy. Its rotation time constant of 40 ns indicates an elongated structure, which is consistent with a prolate ellipsoid of 100 A for the long axis and 40 A for the short axis. The time constant can also be fitted by a cylinder of length 78 A and diameter 37 A, which is consistent with nuclease protection data reported on repressor-operator complexes, if the cylinder axis is aligned parallel to the DNA axis. Addition of tetracycline induces changes of the limit dichroism but very little change of the rotation time constant. The rotation time constants observed for the operator DNA fragments show some deviations from the values expected from their contour length; however, these deviations remain relatively small. Formation of repressor-operator complexes leads to some increase of the DNA rotation time constants. Simulations by bead models demonstrate that these time constants can be explained without any major change of the hydrodynamic dimension of the components. The data for the complexes are fitted by bead models with smooth bending of the DNA corresponding to a radius of curvature of 500 A, but at the given accuracy, we cannot rule out that the DNA in the complex remains straight or is bent to a smaller radius of approximately 400 A. Thus, binding of the Tet repressor, which is a helix-turn-helix protein as judged from its sequence, to its operator seems to induce minor bending but does not induce strong bending of the DNA double helix. 相似文献
30.
Helix-coil dynamics of a Z-helix hairpin 总被引:1,自引:0,他引:1
The helix–coil transition of a Z-helix hairpin formed from d(C-G)5T4(C-G)5 has been characterized by equilibrium melting and temperature jump experiments in 5M NaClO4 and 10 mM Na2HPO4, pH 7.0. The melting curve can be represented by a simple all-or-none transition with a midpoint at 81.6 ± 0.4°C and an enthalpy change of 287 ± 15 kJ/mole. The temperature jump relaxation can be described by single exponentials at a reasonable accuracy. Amplitudes measured as a function of temperature provide equilibrium parameters consistent with those derived from equilibrium melting curves. The rate constants of Z-helix formation are found in the range from 1800 s?1 at 70°C to 800 s?1 at 90°C and are associated with an activation enthalpy of ?(50 ± 10) kJ/mole, whereas the rate constants of helix dissociation are found in the range from 200 s?1 at 70°C to 4500 s?1 at 90°C with an activation enthalpy +235 kJ/mole. These parameters are consistent with a requirement of 3–4 base pairs for helix nucleation. Apparently nucleation occurs in the Z-helix conformation, because a separate slow step corresponding to a B to Z transition has not been observed. In summary, the dynamics of the Z-helix–coil transition is very similar to that of previously investigated right-handed double helices. 相似文献