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At least 487 records · Page 27Linked to original sources

PubMed2003

Dynamics of RNase-A and S-protein: a molecular dynamics simulation of the transition toward a folding intermediate.

The description at atomic level of protein folding is an ambitious goal in biophysics, particularly because of the difficulty in obtaining structural information on unfolded states. Computer simulations can contribute in achieving this goal. Here we report the results of a 10-ns comparative simulation on bovine ribonuclease A and its S-protein, obtained by removal from the native molecule of the first 20 residues, the so-called S-peptide. The atomic trajectories have been analyzed by standard procedures and by applying concepts previously developed for disordered systems. Furthermore, we used a novel approach, described in the preceding paper, to represent graphically the energy landscape of the simulated systems. Relative to RNase-A, the S-protein, while largely maintaining its structural organization, displays an increased structural flexibility, it gains ergodicity and its core loses order, thus indicating that the removal of the S-peptide from ribonuclease A triggers the transition to a folding intermediate with reduced compactness. This finding also has biochemical relevance since the S-protein is recognized as not properly folded by the machinery responsible for the control of the folding quality in the endoplasmic reticulum.

Computer Simulation↗

PubMed2000

Two dimensional inverse imaging (2DII) of current sources in magnetoencephalography.

A new magnetoencephalographic (MEG) technique for imaging the cortical distribution of neuronal activity is described. An iterative algorithm is employed, which successively alters an initial estimate of cortical source structure until it corresponds to the measured magnetic field data. In this new technique, the continuum of electrical activity across the cortical surface is modeled as a dense grid of thousands of single equivalent current dipoles. MEG imaging of both compact and extended sources is facilitated by a wavelet-like transformation of the source space into a sequence of successively smaller composite source structures. Two of these composite source structures are combined during each iterative step to generate an improved estimate of the cortical source structure. Thus, inversion of the complete gain matrix corresponding to thousands of cortical sources is not performed. The technique requires only moderate PC based resources even for very large source grids. In contrast to minimum norm MEG imaging methods, this new algorithm is insensitive to random noise in the data. If available, prior knowledge of source structure from other imaging techniques, such as PET, MRI and fMRI, is easily incorporated as additional constraints on the source structure solution. Source images solutions corresponding to simulated data are presented. In addition, the technique is applied to source imaging of real MEG data incorporating cortical structure from volumetric MRI data. These results demonstrate the capability of our new technique for imaging combinations of compact and extended source structures.

Algorithms↗

PubMed2003

Increased rigidity of eglin c at acidic pH: evidence from NMR spin relaxation and MD simulations.

To gain physical insights into how proteins respond to changes in pH, the picosecond to nanosecond time scale dynamics of the small serine protease inhibitor eglin c have been studied by NMR spin relaxation experiments and MD simulations under two pH solution conditions, pH 7 and 3. Like many proteins, eglin c is destabilized by a lowering of the pH, although it retains enough stability to maintain its native conformation at pH 3. Backbone (15)N relaxation results show comparable global tumbling times (tau(m)) and model-free order parameters (S(2)) under the two pH conditions, indicating that the molecule maintains its overall molecular shape and structure at low pH, although the backbone rigidity is slightly increased ( / = 0.6%). In contrast, the side-chain methyl dynamics, as measured from (2)H relaxation experiments, show a substantial increase in rigidity at lower pH ( / = 14.8%). Molecular dynamics simulations performed at these pH states produce results consistent with NMR measurements, showing that the two methods are in qualitative agreement. Although a full accounting of the physical basis for the concurrent conformational rigidification and destabilization at low pH requires further investigation, the high level of detail in the MD simulations provides a potential molecular mechanism: the breaking of the hydrogen bond between the side chains of Asp46 and Arg53, and changes in electrostatic interactions, appear to allow the binding loop to move closer to the core part of the protein, resulting in a more compact structure at low pH. This more compact structure may be responsible for the increased level of restriction of molecular motion. As these findings show, the stability of a molecular structure is distinct from its conformational rigidity, and the two can even change in opposite directions, against naïve expectation.

Animals↗

PubMedDate not supplied

Conformations of nicotinamide adenine dinucleotide (NAD(+)) in various environments.

Enzymes bind NAD(+) in extended conformations and yet NAD(+) exists in aqueous solution as a compact, folded molecule. Thus, NAD(+) conformation is environment dependent. In an attempt to investigate the effects of environmental changes on the conformation of NAD(+), a series of molecular dynamics simulations in different solvents was performed. The solvents investigated (water, DMSO, methanol and chloroform) represented changes in relative permittivity and hydrophobic character. The simulations predicted folded conformations of NAD(+) to be more stable in water, DMSO and methanol. In contrast, extended conformations of NAD(+) were observed to be more stable in chloroform. Furthermore, the extended conformations observed in chloroform were similar to conformations of NAD(+) bound to enzymes. In particular, a large separation between the aromatic rings and a strong interaction between the pyrophosphate and nicotinamide groups were observed. The implications of these observations for the recognition of NAD(+) by enzymes is discussed. It is argued that a hydrophobic environment is important for stabilizing unfolded conformations of NAD(+).

Dimethyl Sulfoxide↗

PubMed1998

Autocorrelation function and power spectrum of two-state random processes used in neurite guidance.

During development neurons extend and retract cytoskeletal structures, chiefly microtubules and filopodia, to process informational cues from the extracellular environment and thereby guide growth cone migration toward an appropriate synaptic partner. This cytoskeleton-based exploration is achieved by stochastic switching, with microtubules and filopodia alternating between growing and shortening phases apparently at random. If stabilizing signals are not detected during the growth phase, then the structures switch to a shortening state, from which they can again return to a growth phase, and so forth. A useful means of characterizing these stochastic processes in a model-independent way is by autocorrelation and spectral analysis. Previously, we compared experiment to theory by performing Monte Carlo simulations and computing the autocorrelation function and power spectrum from the simulated dynamics, an approach that is computationally intensive and requires recalculation whenever model parameters are changed. Here we present analytical expressions for the autocorrelation function and power spectrum, which compactly characterize microtubule and filopodial dynamics based on the stochastic, two-state model. The model assumes that the phase times are of variable duration and gamma-distributed, consistent with experimental evidence for microtubules assembled in vitro from purified tubulin. The analytical expressions permit the precise quantitative characterization of changes in microtubule and filopodial searching behavior corresponding to changes in the shape of the gamma distribution.

Animals↗

PubMedDate not supplied

Simulations of voltage clamping poorly space-clamped voltage-dependent conductances in a uniform cylindrical neurite.

Significant error is made by using a point voltage clamp to measure active ionic current properties in poorly space-clamped cells. This can even occur when there are no obvious signs of poor spatial control. We evaluated this error for experiments that employ an isochronal I(V) approach to analyzing clamp currents. Simulated voltage clamp experiments were run on a model neuron having a uniform distribution of a single voltage-gated inactivating ionic current channel along an elongate, but electrotonically compact, process. Isochronal Boltzmann I(V) and kinetic parameter values obtained by fitting the Hodgkin-Huxley equations to the clamp currents were compared with the values originally set in the model. Good fits were obtained for both inward and outward currents for moderate channel densities. Most parameter errors increased with conductance density. The activation rate parameters were more sensitive to poor space clamp than the I(V) parameters. Large errors can occur despite "normal"-looking clamp curves.

Action Potentials↗

PubMed1978

Analysis of the penetrable space within the nucleus.

Radioactive glycogen molecules have been used as passive probes to compare cavity systems within nuclei and isolated chromatin. Isolated chromatin was found to possess a narrow range of microspaces with mean effective diameters between 4.0 and 4.5 nm (40 and 45 A) depending on shape assumptions. Intact nuclei contained a far larger class of free spaces with average diameters in the order of 11.0-15.0 nm. This clearly shows that DNase-I (diam. 4.1 nm) can penetrate and occupy a large proportion of nuclear space even though this enzyme does not readily attack the undisturbed nuclear structure. A structure which simulated the pattern of penetrability and incorporated other known properties of chromatin was used to explain this DNase-I resistance of intact nuclei in terms of an ordered, compact, local structure interspersed by much larger spaces. A system for this local packing is suggested and the functional implications of this type of organization considered.

Animals↗

PubMed2007

Compact system description for systems comprising a tilted plane parallel plate.

A paraxial model describing the astigmatism generated by a plane-parallel plate is derived. This model fits the framework of the 4x4 matrix formalism that Arsenault used to describe cylindrical lenses. The framework including this new model is used to build a compact system description of a plane-parallel plate combined with a cylindrical lens, from which several imaging properties are derived. Calculation results are compared with ray-trace simulation results and measurements. Both the ray-trace and the experimental results are in excellent agreement with the calculated results.

Journal Article↗

PubMed2006

NMR structure of the p63 SAM domain and dynamical properties of G534V and T537P pathological mutants, identified in the AEC syndrome.

The p63 protein is crucial for epidermal development, and its mutations cause the extrodactyly ectodermal dysplasia and cleft lip/palate syndrome. The three-dimensional solution structure of the p63 sterile alpha-motif (SAM) domain (residues 505-579), a region crucial to explaining the human genetic disease ankyloblepharonectodermal dysplasia-clefting syndrome (AEC), has been determined by nuclear magnetic resonance spectroscopy. The structure indicates that the domain is a monomer with the characteristic five-helix bundle topology observed in other SAM domains. It includes five tightly packed helices with an extended hydrophobic core to form a globular and compact structure. The dynamics of the backbone and the global correlation time of the molecule have also been investigated and compared with the dynamical properties obtained through molecular dynamics simulation. Attempts to purify the pathological G534V and T537P mutants, originally identified in AEC, were not successful because of the occurrence of unspecific proteolytic degradation of the mutated SAM domains. Analysis of the structural dynamic properties of the G534V and T537P mutants through molecular dynamics simulation and comparison with the wild type permits detection of differences in the degree of freedom of individual residues and discussion of the possible causes for the pathology.

Abnormalities, Multiple↗

PubMed2005

Effect of stress ratio on the fatigue behaviour of compact bone.

During the fatigue process of bone, cracks generally initiate from the inherent defects existing in the bone. The fatigue lives of bone specimens at different stress levels as well as at different stress ratios R were evaluated using a computer simulation in which the crack propagation behaviour initiated from the inherent defects in the bone are herein considered. The S-N curves as well as the distributions of fatigue lives obtained by the simulations accurately conform with the experimental results. With the strain threshold epsilon(max) representing fatigue failure of the bone specimen, the values of 1500 microepsilon for R = -1, 2500 microepsilon for R = 0.1 and 4000 microepsilon for R = 10 were extrapolated from the simulations. These values conform with experimental values reported in the literature. Such conformity indicates that the strain threshold for fatigue failure is associated with the threshold value for crack propagation.

Animals↗

PubMed2026

In silico identification of DNMT1 inhibitors from the PlantCyc database through computational approach to assess the anti-cancer potential of nutraceutical compounds in breast cancer.

Breast cancer accounts for a disproportionate share of global cancer-related deaths, with 670,000 fatalities and 2.3 million new diagnoses recorded in women during 2022 alone. Existing treatment modalities carry considerable toxicity burdens, and resistance to available agents remains an unresolved clinical problem. DNA methyltransferase 1 (DNMT1), the enzyme chiefly responsible for maintaining genome-wide methylation patterns during DNA replication, has been mapped out as a high-value target in breast cancer because its dysregulation silences tumour suppressor genes through promoter hypermethylation. The present work involves hierarchical in silico workflow to screen 4549 plant-derived compounds from the PlantCyc database (v16.0.3) against the human DNMT1 catalytic domain (PDB ID: 4WXX). Ten top-scoring compounds were taken forward for molecular docking via AutoDock Vina; Quercetin and Kaempferol both recorded the highest binding affinities at -9.5 kcal/mol, Wogonin (-9.3 kcal/mol) and Xanthohumol (-8.1 kcal/mol) also emerged as strong binders. Pharmacokinetic evaluation using ADMET-AI confirmed that all 10 compounds met Lipinski's rule of five, with human intestinal absorption values at or above 0.98. Wogonin and Xanthohumol were selected for a 100 ns all-atom molecular dynamics (MD) simulation in GROMACS due to their well-rounded ADMET profiles and limited existing data on their specific interactions with DNMT1 in breast cancer. Across all measured trajectory metrics, backbone RMSD, residue fluctuation, radius of gyration, solvent-accessible surface area, and intermolecular hydrogen bond count, Wogonin formed a more stable, compact complex. These findings suggest that Wogonin and Xanthohumol are non-toxic nutraceutical candidates suitable for DNMT1 targeted epigenetic therapy, with computational foundation strong enough to facilitate future in vitro and in vivo validation work.

Humans↗

PubMed1992

PETSIM: Monte Carlo simulation of all sensitivity and resolution parameters of cylindrical positron imaging systems.

Monte Carlo simulation techniques are applied to track the annihilation photons from positron decay, and store the photon histories. Reasonably realistic models of the isotope distribution in the brain and heart during typical PET studies, as well as the traditional phantoms used for measuring PET scanner performance can be built out of up to 10 hollow or solid cylinders. Separate programs model the source distribution and its attenuation characteristics, the collimators and the detectors. These modules are connected by compact gamma history files which are stored on disc or tape. Over 50 million gamma ray histories can be saved on a 1 Gbyte disc, representing the decay of several billion atoms. This allows for good precision even for single thin slices in scanners with wide axial acceptance. The simulation results include spectrum analysis, sensitivity to true coincident events, scattered coincident and single rays, and the effects on these parameters of detector dead time. The storage of intermediate results on tape reduces simulation time, since most common source geometries need be generated only once. The sensitivities in multi-slice systems are presented as matrices of coincident crystal planes. The matrix shows the true count sensitivity and the scatter fraction together for each valid combination of planes. This presentation is very useful for assessing the effects of various degrees of inter-plane collimation. The spatial resolution analysis includes the effects of positron range, non-collinearity of the gamma rays, multiple interaction within the detectors, and the effects of quantization into single crystals in multiple-crystal block detectors. Each of these effects can be turned on or off without repeating the simulation. Both in-plane and axial resolutions are calculated as a function of location of the positron-emitting nucleus and the angle of incidence of gamma rays on the crystals. Single crystals, blocks and crystals with depth of interaction encoding can be specified, as can the method of backprojection (planar, or 3D), so that the detector geometry can be optimized.

Computer Simulation↗

PubMed2004

BNCT dose distribution in liver with epithermal D-D and D-T fusion-based neutron beams.

Recently, a new application of boron neutron capture therapy (BNCT) treatment has been introduced. Results have indicated that liver tumors can be treated by BNCT after removal of the liver from the body. At Lawrence Berkeley National Laboratory, compact neutron generators based on (2)H(d,n)(3)He (D-D) or (3)H(t,n)(4)He (D-T) fusion reactions are being developed. Preliminary simulations of the applicability of 2.45 MeV D-D fusion and 14.1 MeV D-T fusion neutrons for in vivo liver tumor BNCT, without removing the liver from the body, have been carried out. MCNP simulations were performed in order to find a moderator configuration for creating a neutron beam of optimal neutron energy and to create a source model for dose calculations with the simulation environment for radiotherapy applications (SERA) treatment planning program. SERA dose calculations were performed in a patient model based on CT scans of the body. The BNCT dose distribution in liver and surrounding healthy organs was calculated with rectangular beam aperture sizes of 20 cm x 20 cm and 25 cm x 25 cm. Collimator thicknesses of 10 and 15 cm were used. The beam strength to obtain a practical treatment time was studied. In this paper, the beam shaping assemblies for D-D and D-T neutron generators and dose calculation results are presented.

Boron Neutron Capture Therapy↗

PubMedDate not supplied

In vitro gene delivery by degraded polyamidoamine dendrimers.

Transfection of cultured cells has been reported using complexes between DNA and spherical cationic polyamidoamine polymers (Starburst dendrimers) that consist of primary amines on the surface and tertiary amines in the interior. The transfection activity of the dendrimers is dramatically enhanced (> 50-fold) by heat treatment in a variety of solvolytic solvents, e.g., water or butanol. Such treatment induces significant degradation of the dendrimer at the amide linkage, resulting in a heterodisperse population of compounds with molecular weights ranging from the very low (< 1500 Da) to several tens of kilodaltons. The compound facilitating transfection is the high molecular weight component of the degraded product and is denoted as a "fractured" dendrimer. Transfection activity is related both to the initial size of the dendrimer and its degree of degradation. Fractured dendrimers exhibit an increased apparent volume change as measured by an increase in the reduced viscosity upon protonation of the terminal amines as pH is reduced from 10.5 to 7.2 whereas intact dendrimers do not. Dendrimers with defective branching have been synthesized and also have improved transfection activity compared to that of the intact dendrimers. For a series of heat-treated dendrimers we observe a correlation between transfection activity and the degree of flexibility, computed with a random cleavage simulation of the degradation process. We suggest that the increased transfection after the heating process is principally due to the increase in flexibility that enables the fractured dendrimer to be compact when complexed with DNA and swell when released from DNA.

DNA↗

PubMed2000

Comparison of different techniques for obturating experimental internal resorptive cavities.

Forty extracted maxillary central incisors were instrumented at the working length to a #50 file. The roots were sectioned transversely with a diamond disk at 7 mm from the anatomical apex. At the opening of the root canal of each section, hemicircular cavities were drilled with a specially designed bur. The corresponding root sections were cemented with glue, thus obtaining root canals with similar cavities that simulated internal resorptions. Teeth were embedded in plaster casts to facilitate their handling. The specimens were randomly separated into four groups of 10. The following obturation techniques were evaluated: lateral compaction (group A), hybrid technique (group B), Obtura II (group C), and Thermafil (group D). AH26 was used as the sealer. After obturation, the plaster was removed and the teeth were radiographed in buccolingual and mesiodistal directions to evaluate the quality of the obturation at the IRC. The incisors were then cut with a scalpel at the same level as the previous section, to examine, under a stereomicroscope, the type of material that filled the IRC. Obtura II gave the best results and in most of the specimens obturated with this technique, the IRC were filled mainly with gutta-percha. Statistical analysis of the data indicated that the differences between group C and the other groups were significant (P < 0.05).

Bismuth↗

PubMed1999

Observational Test of Environmental Effects on the Local Group Dwarf Spheroidal Galaxies.

In this Letter, we examine whether tidal forces exerted by the Galaxy or M31 have an influence on the Local Group dwarf spheroidal galaxies (dSph's) that are their companions. We focus on the surface brightness profiles of the dSph's, especially their core radii, because it is suggested, based on the numerical simulations, that tidal disturbance can make core radii extended. We examine the correlation for the dSph's between the distances from their parent galaxy (the Galaxy or M31) and the compactnesses of their surface brightness profiles by using a parameter C defined newly in this Letter. Consequently, we find no significant correlation. We make some remarks on the origin of this result by considering three possible scenarios-the tidal picture, the dark matter picture, and the heterogeneity of the group of dSphs-each of which has been often discussed as a way of understanding the fundamental properties and formation processes of dSphs.

Journal Article↗

PubMed2005

Clusters of mobile molecules in supercooled water.

We study the spatially heterogeneous dynamics in water via molecular dynamics simulations using the extended simple point charge potential. We identify clusters formed by mobile molecules and study their properties. We find that these clusters grow in size and become more compact as temperature decreases. We analyze the probability density function of cluster size, and we study the cluster correlation length. We find that clusters appear to be characterized by a fractal dimension consistent with that of lattice animals. We relate the cluster size and correlation length to the configurational entropy, S(conf). We find that these quantities depend weakly on 1/ S(conf). In particular, the linearity found between the cluster mass n(*) and 1/ S(conf) suggests that n(*) may be interpreted as the mass of the cooperatively rearranging regions that form the basis of the Adam-Gibbs approach to the dynamics of supercooled liquids. We study the motion of molecules within a cluster, and find that each molecule preferentially follows a neighboring molecule in the same cluster. Based on this finding we hypothesize that stringlike cooperative motion may be a general mechanism for molecular rearrangement of complex, as well as simple liquids. By mapping each equilibrium configuration onto its corresponding local potential energy minimum or inherent structure (IS), we are able to compare the mobile molecule clusters in the equilibrium system with the molecules forming the clusters identified in the transitions between IS. We find that (i) mobile molecule clusters obtained by comparing different system configurations and (ii) clusters obtained by comparing the corresponding IS are completely different for short time scales, but are the same on the longer time scales of diffusive motion.

Journal Article↗

PubMed2006

Fluids of clusters in attractive colloids.

We show that colloidal particles with attractive interactions induced by a nonadsorbing polymer exhibit a stable phase consisting of a fluid of clusters of particles. This phase persists even in the absence of any long-range repulsion due to charge, contrary to expectations based on simulation and theory. Cluster morphology depends strongly on the range of the interparticle attraction: With a shorter range, clusters are tenuous and branched; with a longer range, they are more compact.

Journal Article↗