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PubMedDate not supplied

Characterization of skin penetration processes of organic molecules using molecular similarity and QSAR analysis.

Molecular similarity and QSAR analyses have been used to develop compact, robust, and definitive models for skin penetration by organic compounds. The QSAR models have been sought to provide an interpretation and characterization of plausible molecular mechanisms of skin penetration. A training set of 40 structurally diverse compounds were selected to be representative of a parent set of 152 compounds in terms of both structural diversity and range in measured skin penetration. The subset of 40 compounds was used in a series of QSAR analyses in the search for the most significant, compact, and straightforward skin penetration QSAR models. Molecular dynamics simulations were employed to determine a set of MI (membrane-interaction) descriptors for each test compound (solute) interacting with a model DMPC monolayer membrane model. The MI-QSAR models may capture features of cellular membrane lateral transverse transport involved in the overall skin penetration process by organic compounds. An additional set of intramolecular solute descriptors, the non-MI-QSAR descriptors, were computed and added to the trial pool of descriptors for building QSAR models. All QSAR models were constructed using multidimensional linear regression fitting and a genetic algorithm optimization function. QSAR models were constructed using only non-MI-QSAR descriptors and using a combination of both these descriptor sets. It was found that a combination of non-MI-QSAR and MI-QSAR descriptors yielded the optimum models, not only with respect to the statistical measures of fit but also regarding model predictivity.

Cell Membrane↗

PubMed2004

Analysis of the evolution of granular stress-strain and voidage states based on DEM simulations.

We review and discuss the results of our granular-dynamics simulations of the time evolution of the microstructure of compact granular beds as found in pouring, in hopper filling and discharge, and in a shear cell. These systems are mainly quasi-static. However, it is also common to encounter localized 'shear zones' with significant velocity/voidage fluctuations and high bulk-strain gradients. These narrow-banded zones are separated from near-static regions by sharp, discontinuous changes of bulk stress and voidage. Within these bands the granular assembly undergoes a transition from the quasi-static to the inertial state, where enduring particle contacts are increasingly replaced by collisional ones. We focus on the discrete particle origins of this inhomogeneous yield/flow behaviour. We show the usefulness of analysing the local evolution in terms of relative rotation of the grains which is observed to cause rapid local bulk dilation responsible for setting off avalanches near free-surface boundaries and protracted bulk-failure planes in confined static assemblies. We also present some evidence to suggest that allowing for effective continuous particle-particle interactions could approximate observed effects attributable to particle shape and surface roughness. Wavelet analyses have been applied successfully to generate the variations in periodicity and the relative sequence of evolution of the stress, strain-rate and voidage states in avalanching granular heaps and in the wall region of axially symmetric hopper flows.

Journal Article↗

PubMed1996

Neural networks as a tool for compact representation of ab initio molecular potential energy surfaces.

Ab initio quantum chemical calculations of molecular properties such as, e.g., torsional potential energies, require massive computational effort even for moderately sized molecules, if basis sets with a reasonable quality are employed. Using ab initio data on conformational properties of the cofactor (6R,1'R,2'S)-5,6,7,8-tetrahydrobiopterin, we demonstrate that error backpropagation networks can be established that efficiently approximate complicated functional relationships such as torsional potential energy surfaces of a flexible molecule. Our pilot simulations suggest that properly trained neural networks might provide an extremely compact storage medium for quantum chemically obtained information. Moreover, they are outstandingly comfortable tools when it comes to making use of the stored information. One possible application is demonstrated, namely, computation of relaxed torsional energy surfaces.

Biopterins↗

PubMed2006

Secondary structure determines protein topology.

Using a test set of 13 small, compact proteins, we demonstrate that a remarkably simple protocol can capture native topology from secondary structure information alone, in the absence of long-range interactions. It has been a long-standing open question whether such information is sufficient to determine a protein's fold. Indeed, even the far simpler problem of reconstructing the three-dimensional structure of a protein from its exact backbone torsion angles has remained a difficult challenge owing to the small, but cumulative, deviations from ideality in backbone planarity, which, if ignored, cause large errors in structure. As a familiar example, a small change in an elbow angle causes a large displacement at the end of your arm; the longer the arm, the larger the displacement. Here, correct secondary structure assignments (alpha-helix, beta-strand, beta-turn, polyproline II, coil) were used to constrain polypeptide backbone chains devoid of side chains, and the most stable folded conformations were determined, using Monte Carlo simulation. Just three terms were used to assess stability: molecular compaction, steric exclusion, and hydrogen bonding. For nine of the 13 proteins, this protocol restricts the main chain to a surprisingly small number of energetically favorable topologies, with the native one prominent among them.

Computer Simulation↗

PubMed2003

Microdamage and mechanical behaviour: predicting failure and remodelling in compact bone.

This paper reports on the development of a theoretical model to simulate the growth and repair of microdamage in bone. Unlike previous theories, which use simplified descriptions of damage, this approach models each individual microcrack explicitly, and also models the basic multicellular units (BMUs) that repair cracks. A computer simulation has been developed that is capable of making a variety of predictions. Firstly, we can predict the mechanical behaviour of dead bone in laboratory experiments, including estimates of the number of cycles to failure and the number and length of microcracks during fatigue tests. Secondly, we can predict the results of bone histomorphometry, including such parameters as BMU activation rates and the changing ratio of primary to secondary bone during ageing. Thirdly, we can predict the occurrence of stress fractures in living bone: these occur when the severity of loading is so great that cracks grow faster than they can be repaired. Finally, we can predict the phenomenon of adaptation, in which bone is deposited to increase cortical thickness and thus prevent stress fractures. In all cases results compare favourably with experimental and clinical data.

Adaptation, Physiological↗

PubMed2026

Computational discovery of emodin-based anthraquinones as PARP-1 inhibitors with relevance to ovarian and prostate cancer.

Cancer is a disease characterized by genomic instability and aberrant DNA repair. Poly (ADP-ribose) polymerase-1 (PARP-1) represents a well-established therapeutic target, particularly in ovarian and prostate cancer. However, the currently approved PARP inhibitors face challenges such as resistance, toxicity, and reduced efficacy. The search for alternative scaffolds has therefore become increasingly urgent. In this study, we used an integrated approach combining computer-aided methods to search for potential lead compounds among emodin-based anthraquinone derivatives as PARP-1 inhibitors. Using a PASS-based QSAR approach, drug-likeness prediction, and in silico ADMET assessment, we pre-screened a large set of anthraquinones and identified several potential hits for interaction with PARP-1. These hits were studied using molecular docking with the PARP-1 catalytic domain (PDB ID: 7KK4). The most stable and compact complexes were further explored by 500 ns molecular dynamics (MD) simulations and various dynamic properties (RMSD, RMSF, Rg, SASA, MolSA, hydrogen bonds, PCA, DCCM). The key finding of this study is that several emodin-derived anthraquinones exhibited binding behavior and ADMET profiles comparable to, or better than, the reference PARP-1 inhibitor. Among them, CID-10425624 emerged as the most promising candidate, exhibiting stable binding, reduced conformational fluctuation, compact complex formation, persistent hydrogen-bond interactions, and enhanced dynamic residue correlations within the PARP-1 catalytic domain. These findings suggest that the anthraquinone scaffold can provide a valuable starting point for developing structurally distinct PARP-1 inhibitors. In summary, this study identified several emodin-derived anthraquinones, particularly CID-10425624, as computationally prioritized lead candidates for PARP-1 inhibition, providing a novel anthraquinone-based scaffold for further experimental validation and optimization.

Anthraquinones↗

PubMed2004

A numerical approach to the selection of basis for frame-encoded MRI.

A numerical approach was proposed to systematically investigating the suitability of various bases for frame-encoded magnetic resonance imaging (MRI). Several basic requirements were established for the ideal encoding frame basis. Three different orders of spline bases were extensively examined with simulation of 2-dimensional MRI. Analyses of imaging time and signal-to-noise ratio showed that the compactly supported quadratic spline basis is a strong candidate for high quality MRI with a short imaging time. The simulations also suggested that encoding with three levels of resolution is the best choice.

Algorithms↗

PubMed2005

Real-time near-infrared monitoring of content uniformity, moisture content, compact density, tensile strength, and Young's modulus of roller compacted powder blends.

A method for real-time in-line near-infrared (NIR) monitoring of roller compaction is reported. Multivariate analysis using partial least square projections to latent structures (PLS) was used to relate the spectral data with key compact attributes: content uniformity, moisture content, relative density, tensile strength, and Young's modulus. NIR calibration curves were generated using the spectral data collected on simulated ribbons, that is, tablets prepared under uni-axial compression, and tested on the data collected on another set of simulated ribbons and by monitoring the ribbons as they exited the roller compactor. For all compact attributes, the NIR predicted values agreed well with the values measured using a reference method.

Acetaminophen↗

PubMed2000

On the unfolding of alpha-lytic protease and the role of the pro region.

Molecular dynamics simulations of alpha-lytic protease (alphaLP) alone and complexed with its pro region (PRO) are performed to understand the origin of its high unfolding (and folding) barrier when it is alone and how the pro region lowers this barrier. At room temperature, alphaLP exhibits lower dynamic fluctuations than alpha-chymotrypsin. Simulation of PRO alone led to reorientation of its N terminal helix and collapse to a more compact state. A model for the uncleaved proenzyme was built and found to be stable in the time scale of the simulations. Energetic analysis suggests that the origin of strain in the uncleaved proenzyme compared with the cleaved complex is in the intramolecular backbone electrostatic interactions of the cleaved strand. In high temperature simulations, the interaction of the long beta hairpin of the enzyme with the C terminal beta sheet of PRO is among the most stable in the complex and a likely "nucleation site" for folding. In the course of unfolding, the C terminal tail of PRO is sometimes observed to intervene between the long hairpin and the aspartate loop of the enzyme, perhaps thereby lowering the energy barrier for separation of the two hairpins. Tighter interactions at the interface between the enzyme and its pro region are also occasionally observed, providing an additional mechanism for unfolding catalysis. Simulations of a mutant enzyme where the buried ion pair residues R102 and D142 were replaced by W and L, respectively, did not display any distinguishable behavior compared with the wild type.

Models, Molecular↗

PubMed1991

Molecular structure matching by simulated annealing. IV. Classification of atom correspondences in sets of dissimilar molecules.

A set of 6 molecules, active at the benzodiazepine GABAA site are matched pairwise with one member of the set in turn. Matchings are performed by simulated annealing using null correspondences to reject poorly matched atom positions. Cluster analysis is employed to identify molecular similarities after an optimal molecular superimposition has been discovered. A statistic for the compactness of clustered atom positions is suggested. The introduction of null correspondences causes the clusters of matched atoms to become more compact.

Benzodiazepines↗

PubMed2006

Calculation of the entropy and free energy of peptides by molecular dynamics simulations using the hypothetical scanning molecular dynamics method.

Hypothetical scanning (HS) is a method for calculating the absolute entropy S and free energy F from a sample generated by any simulation technique. With this approach each sample configuration is reconstructed with the help of transition probabilities (TPs) and their product leads to the configuration's probability, hence to the entropy. Recently a new way for calculating the TPs by Monte Carlo (MC) simulations has been suggested, where all system interactions are taken into account. Therefore, this method--called HSMC--is in principle exact where the only approximation is due to insufficient sampling. HSMC has been applied very successfully to liquid argon, TIP3P water, self-avoiding walks on a lattice, and peptides. Because molecular dynamics (MD) is considered to be significantly more efficient than MC for a compact polymer chain, in this paper HSMC is extended to MD simulations as applied to peptides. Like before, we study decaglycine in vacuum but for the first time also a peptide with side chains, (Val)(2)(Gly)(6)(Val)(2). The transition from MC to MD requires implementing essential changes in the reconstruction process of HSMD. Results are calculated for three microstates, helix, extended, and hairpin. HSMD leads to very stable differences in entropy TDeltaS between these microstates with small errors of 0.1-0.2 kcal/mol (T=100 K) for a wide range of calculation parameters with extremely high efficiency. Various aspects of HSMD and plans for future work are discussed.

Chemistry, Physical↗

PubMed1997

Refinement of the NMR solution structure of the gamma-carboxyglutamic acid domain of coagulation factor IX using molecular dynamics simulation with initial Ca2+ positions determined by a genetic algorithm.

A genetic algorithm (GA) successfully identified the calcium positions in the crystal structure of bovine prothrombin fragment 1 bound with calcium ions (bf1/Ca). The same protocol was then used to determine the calcium positions in a closely related fragment, the Gla domain of coagulation factor IX, the structure of which had previously been determined by NMR spectroscopy in the presence of calcium ions. The most frequently occurring low-energy structure found by GA was used as the starting structure for a molecular dynamics refinement. The molecular dynamics simulation was performed using explicit water and the Particle-Mesh Ewald method to accommodate the long-range electrostatic forces. While the overall conformation of the NMR structure was preserved, significant refinement is apparent when comparing the simulation average structure with its NMR precursor in terms of the N-terminal (Tyr1-N) network, the total number of hydrogen bonds, the calcium ion coordinations, and the compactness of the structure. It is likely that the placement of calcium ions in the protein is critical for refinement. The calcium ions apparently induce structural changes during the course of the simulation that result in a more compact structure.

1-Carboxyglutamic Acid↗

PubMed1991

Structural dynamics of calmodulin and troponin C.

We present the results of computational simulation studies of the structures of calmodulin (CAM) and troponin C (TNC). Possible differences between the structures of these molecules in the crystal and in solution were suggested by results from some recent experimental studies, which implied that their conformations in solution may be more compacted than the characteristic dumbbell shape observed in the crystal. The molecular dynamics simulations were carried out with the CHARMM system of programs, and the environment was modeled with a distance-dependent dielectric permittivity and discrete water molecules surrounding the proteins at starting positions identified in the crystals of CAM and TNC. Methods of macromolecular structure analysis, including linear distance plots, distance matrices and a matrix representation of hydrogen bonding, were used to analyze the nature, the extent and the source of structural differences between the computed structures of the molecules and their conformations in the crystal. Following the longest simulation, in which intradomain structure was conserved, the crystallographically observed dumbbell structure of the molecule changed due to a kinking or bending in the region of the central tether helix connecting the two Ca(2+)-binding domains which moved into close proximity. The resulting structure correlates with experimental observations of complexes between CAM and peptides such as melittin and mastoparan. Analysis of the corresponding pair distance distribution functions in comparison to experimental results suggests the dynamic existence of a non-negligible fraction of the compacted structure in aqueous solutions of CAM. In this more nearly globular shape, CAM reveals to the environment two interior pockets that contain a number of hydrophobic residues, in agreement with NMR data suggesting involvement of such residues in the binding of inhibitors and proteins to CAM.

Calcium↗

PubMed2006

Polyelectrolytes in solutions with multivalent salt. Effects of flexibility and contour length.

It has been experimentally observed that trivalent ions are capable of promoting compaction of semi-flexible polyelectrolyte chains. In this work we perform Monte Carlo simulations on single chain model systems with varying chain size and stiffness and evaluate the action of multivalent salt on the chain conformation. It is observed that longer chains tend to achieve relatively more compact conformations than shorter ones, and the dimensions of the collapsed structures do not significantly vary with contour length. The influence of contour length and intrinsic stiffness in the process of ion condensation is studied by analysis of the ion-ion nearest-neighbor distribution. The general trend is an increase of the degree of ion condensation as the chain length increases, in accordance with experimental evidence. A decreased importance of end-effects and, especially, larger volume charge densities are responsible for such behavior. The influence of chain stiffness is nontrivial, and depends on salt concentration. The results emphasize the complex nature of ion-correlation phenomena in flexible or semi-flexible chains and call for the development of more sophisticated analytical theories.

Complex Mixtures↗

PubMed2006

Inferring functional pathways from multi-perturbation data.

BACKGROUND: Recently, a conceptually new approach for analyzing gene networks, the Functional Influence Network (FIN) was presented. The FIN approach uses the measured performance of a given cellular function under different multi-perturbations, to identify the main functional pathways and interactions underlying its processing. Here we present and study an iterative, extended version of FIN, the Functional Influence Network Extractor (FINE), which is specifically geared towards the accurate analysis of sparse cellular systems. We employ it to study a conceptually fundamental question of practical importance--how well should we know the system studied (such that we can predict its performance) so that we can understand its workings (i.e., chart its underlying functional network)? RESULTS AND CONCLUSIONS: The performance of FINE is studied in both simulated and biological sparse systems. It successfully obtains an accurate and compact description of the underlying functional network even with limited data, and outperforms FIN. We show that prior estimates of a system's functional complexity are instrumental in determining how much predictive knowledge is required to accurately chart its underlying functional network. AVAILABILITY: The FINE software is available for download at http://www.cns.tau.ac.il/resc.html.

Algorithms↗

PubMed2005

Tests for the evaluation of ammonium attenuation in MSW landfill leachate by adsorption into bentonite in a landfill liner.

Uncontrolled leachate emissions are one of the key factors in the environmental impact of municipal solid waste (MSW) landfills. The concentration of ammonium, given the anaerobic conditions in traditional landfills, can remain significantly high for a very long period of time, as degradation does not take place and volatilisation is not significant (the pH is not high enough to considerably shift the equilibrium towards un-ionised ammonia). Recent years have witnessed a continuous enhancement of landfill technology in order to minimize uncontrolled emissions into the environment; bottom lining systems have been improved and more attention has been devoted to the study of the attenuation of the different chemicals in leachate in case of migration through the mineral barrier. Different natural materials have been considered for use as components of landfill liners in the last years and tested in order to evaluate the performance of the different alternatives. Among those materials, bentonite is often used, coupled with other materials in two different ways: in addition to in situ soil or in geocomposite clay liner (GCL). A lab-scale test was carried out in order to further investigate the influence of bentonite on the attenuation of ammonium in leachate passing through a landfill liner. Two different tests were conducted: a standardized batch test with pulverized bentonite and a batch test with compacted bentonite. The latter was proposed in order to better simulate the real conditions in a landfill liner. The two tests produced values for the partition coefficient K(d) higher than the average measured for other natural materials usually utilized as components of landfill liners. Moreover, the two tests showed similar results, thus providing a further validation of the suitability of the standard batch test with pulverized bentonite. A thorough knowledge of attenuation processes of ammonium in landfill liners is the basis for the application of risk analysis models for the evaluation of the failure of bottom liners or their components.

Adsorption↗

PubMed1998

Tritium planigraphy: from the accessible surface to the spatial structure of a protein.

The method of tritium planigraphy, which provides comprehensive information on the accessible surface of macromolecules, allows an attempt at reconstructing the three-dimensional structure of a protein from the experimental data on residue accessibility for labeling. The semiempirical algorithm proposed for globular proteins involves (i) predicting theoretically the secondary structure elements (SSEs), (ii) experimentally determining the residue-accessibility profile by bombarding the whole protein with a beam of hot tritium atoms, (iii) generating the residue-accessibility profiles for isolated SSEs by computer simulation, (iv) locating the contacts between SSEs by collating the experimental and simulated accessibility profiles, and (v) assembling the SSEs into a compact model via these contact regions in accordance with certain rules. For sperm whale myoglobin, carp and pike parvalbumins, the lambda cro repressor, and hen egg lysozyme, this algorithm yields the most realistic models when SSEs are assembled sequentially from the amino to the carboxyl end of the protein chain.

Algorithms↗

PubMed2006

High-dimensional model representation of cyclic voltammograms.

Digital simulation costs present an obstacle on the way to high-speed, real-time, on-line theoretical analysis of experimental data in cyclic voltammetry. To overcome this difficulty, we propose to use solution mapping based on a correlated, hierarchical expansion of multivariate functions, known as high-dimensional model representation (HDMR). The nonlinear dependencies of the simulated voltammograms on multiple model parameters are represented in the form of compact look-up tables, from which approximate voltammograms can be calculated rapidly by interpolation, for any model parameter combinations from a predefined domain. Most importantly, the HDMR does not suffer from the problem of the exponential growth of the look-up tables with the number of model parameters. The creation of a solution map requires a single effort of simulating many voltammograms. However, once the map is prepared, it can be stored and reused many times without the need to repeat costly simulations. HDMR maps are created and examined for five examples of cyclic voltammetry models at planar macroelectrodes in a one-dimensional spatial geometry under pure diffusion transport conditions. The usefulness of the maps for rapid visualization and exploration of the effects of the parameters on the voltammograms and for rapid simultaneous estimation of many parameters from cyclic voltammetric data is demonstrated through computational experiments.

Journal Article↗