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PubMed2006

Graph transformation method for calculating waiting times in Markov chains.

We describe an exact approach for calculating transition probabilities and waiting times in finite-state discrete-time Markov processes. All the states and the rules for transitions between them must be known in advance. We can then calculate averages over a given ensemble of paths for both additive and multiplicative properties in a nonstochastic and noniterative fashion. In particular, we can calculate the mean first-passage time between arbitrary groups of stationary points for discrete path sampling databases, and hence extract phenomenological rate constants. We present a number of examples to demonstrate the efficiency and robustness of this approach.

Journal Article↗

PubMed2006

Representation of target-bound drugs by computed conformers: implications for conformational libraries.

BACKGROUND: The increasing number of known protein structures provides valuable information about pharmaceutical targets. Drug binding sites are identifiable and suitable lead compounds can be proposed. The flexibility of ligands is a critical point for the selection of potential drugs. Since computed 3D structures of millions of compounds are available, the knowledge of their binding conformations would be a great benefit for the development of efficient screening methods. RESULTS: Integration of two public databases allowed superposition of conformers for 193 approved drugs with 5507 crystallised target-bound counterparts. The generation of 9600 drug conformers using an atomic force field was carried out to obtain an optimal coverage of the conformational space. Bioactive conformations are best described by a conformational ensemble: half of all drugs exhibit multiple active states, distributed over the entire range of the reachable energy and conformational space.A number of up to 100 conformers per drug enabled us to reproduce the bound states within a similarity threshold of 1.0 angstroms in 70% of all cases. This fraction rises to about 90% for smaller or average sized drugs. CONCLUSION: Single drugs adopt multiple bioactive conformations if they interact with different target proteins. Due to the structural diversity of binding sites they adopt conformations that are distributed over a broad conformational space and wide energy range. Since the majority of drugs is well represented by a predefined low number of conformers (up to 100) this procedure is a valuable method to compare compounds by three-dimensional features or for fast similarity searches starting with pharmacophores. The underlying 9600 generated drug conformers are downloadable from the Super Drug Web site 1. All superpositions are visualised at the same source. Additional conformers (110,000) of 2400 classified WHO-drugs are also available.

Amino Acid Sequence↗

PubMed2002

Identification of determinism in noisy neuronal systems.

Most neuronal ensembles are nonlinear excitable systems. Thus it is becoming common to apply principles derived from nonlinear dynamics to characterize neuronal systems. One important characterization is whether such systems contain deterministic behavior or are purely stochastic. Unfortunately, many methods used to make this distinction do not perform well when both determinism and high-amplitude noise are present which is often the case in physiological systems. Therefore, we propose two novel techniques for identifying determinism in experimental systems. The first, called short-time expansion analysis, examines the expansion rate of small groups of points in state space. The second, called state point forcing, derives from the technique of chaos control. The system state is forced onto a fixed point, and the subsequent behavior is analyzed. This technique can be used to verify the presence of fixed points (or unstable periodic orbits) and to assess stationarity. If these are present, it implies that the system contains determinism. We demonstrate the use and possible limitations of these two techniques in two systems: the Hénon map, a classic example of a chaotic system, and spontaneous epileptiform bursting in the rat hippocampal slice. Identifying the presence of determinism in a physiological system assists in the understanding of the system's dynamics and provides a mechanism for manipulating this behavior.

Action Potentials↗

PubMed2002

Canopy light transmittance in Douglas-fir--western hemlock stands.

We measured vertical and horizontal variation in canopy transmittance of photosynthetically active radiation in five Pseudotsuga menziesii (Mirb.) Franco-Tsuga heterophylla (Raf.) Sarg. (Douglas-fir-western hemlock) stands in the central Cascades of southern Washington to determine how stand structure and age affect the forest light environment. The shape of the mean transmittance profile was related to stand height, but height of mean maximum transmittance was progressively lower than maximum tree height in older stands. The vertical rate of attenuation declined with stand age in both the overstory and understory. A classification of vertical light zones based on the mean and variance of transmittance showed a progressive widening of the bright (low variance and high mean) and transition (high variance and rapid vertical change) zones in older stands, whereas the dim zone (low variance and mean) narrowed. The zone of maximum canopy surface area in height profiles, estimated by inversion of transmittance profiles, changed from relatively high in the canopy in most young stands ("top-heavy") to lower in the canopy in older stands ("bottom-heavy"). In the understory, all stands had similar mean transmittances, but the spatial scale of variation increased with stand age and increasing crown size. The angular distribution of openness was similar in all stands, though the older stands were less open at all angles than the younger stands. Understory openness was generally unrelated to transmittance in the canopy above. Whole-canopy leaf area indices, estimated using three methods of inverting light measurements, showed little correspondence across methods. The observed patterns in light environment are consistent with structural changes occurring during stand development, particularly the diversification of crowns, the creation of openings of various sizes and the elaboration of the outer canopy surface. The ensemble of measurements has potential use in distinguishing forests of differing ages that have similar stature.

Light↗

PubMed2000

Elastic constants from microscopic strain fluctuations

Fluctuations of the instantaneous local Lagrangian strain epsilon(ij)(r,t), measured with respect to a static "reference" lattice, are used to obtain accurate estimates of the elastic constants of model solids from atomistic computer simulations. The measured strains are systematically coarse-grained by averaging them within subsystems (of size L(b)) of a system (of total size L) in the canonical ensemble. Using a simple finite size scaling theory we predict the behavior of the fluctuations as a function of L(b)/L and extract elastic constants of the system in the thermodynamic limit at nonzero temperature. Our method is simple to implement, efficient, and general enough to be able to handle a wide class of model systems, including those with singular potentials without any essential modification. We illustrate the technique by computing isothermal elastic constants of "hard" and "soft" disk triangular solids in two dimensions from Monte Carlo and molecular dynamics simulations. We compare our results with those from earlier simulations and theory.

Journal Article↗

PubMed2002

Propagation inhibition and wave localization in a two-dimensional random liquid medium.

Acoustic propagation and scattering in water containing many parallel air-filled cylinders is studied in an exact manner. Two situations are considered and compared; (1) wave propagating through the array of cylinders, imitating common experimental setups, and (2) wave transmitted from a source located inside the ensemble. We show that waves can be blocked from propagation by disorders in the first scenario, but such an inhibition does not necessarily lead to actual wave localization in the medium. The results indicate that the traditional method may be ambiguous in discerning localization effects. Furthermore, the results reveal the phenomenon of wave localization in a range of frequencies.

Journal Article↗

PubMed2004

Reaction ensemble Monte Carlo technique and hypernetted chain approximation study of dense hydrogen.

In spite of the simple structure of hydrogen, up to now there is no unified theoretical and experimental description of hydrogen at high pressures. Recent results of Z-pinch experiments show a large deviation from those obtained by laser driven ones. Theoretical investigations including ab initio computer simulations show considerable differences at such extreme conditions from each other and from experimental values. We apply the reaction ensemble Monte Carlo technique on one hand and a combination of the hypernetted chain approximation with the mass action law on the other to study the behavior of dense hydrogen at such conditions. The agreement between both methods for the equation of state and for the Hugoniot curve is excellent. Comparison to other methods and experimental results is also performed.

Journal Article↗

PubMed2001

Deterministic chaos and noise in three in vitro hippocampal models of epilepsy.

Recent reports have suggested that chaos control techniques may be useful for electrically manipulating epileptiform bursting behavior in neuronal ensembles. Because the dynamics of spontaneous in vitro bursting had not been well determined previously, analysis of this behavior in the rat hippocampus was performed. Epileptiform bursting was induced in transverse rat hippocampal slices using three experimental methods. Slices were bathed in artificial cerebrospinal fluid containing: (1) elevated potassium ([K+]o= 10.5 mM), (2) zero magnesium, or (3) the GABAA-receptor antagonists bicuculline (20 microM) and picrotoxin (250 microM). The existence of chaos and determinism was assessed using two different analytical techniques: unstable periodic orbit (UPO) analysis and a new technique for estimating Lyapunov exponents. Significance of these results was assessed by comparing the calculations for each experiment with corresponding randomized surrogate data. UPOs of multiple periods were highly prevalent in experiments from all three epilepsy models: 73% of all experiments contained at least one statistically significant period-1 or period-2 orbit. However, the expansion rate analysis did not provide any evidence of determinism in the data. This suggests that the system may be globally stochastic but contains local pockets of determinism. Thus, manipulation of bursting behavior using chaos control algorithms may yet hold promise for reverting or preventing epileptic seizures.

Animals↗

PubMed2005

Cross talk free fluorescence cross correlation spectroscopy in live cells.

Fluorescence correlation spectroscopy (FCS) is now a widely used technique to measure small ensembles of labeled biomolecules with single molecule detection sensitivity (e.g., low endogenous concentrations). Fluorescence cross correlation spectroscopy (FCCS) is a derivative of this technique that detects the synchronous movement of two biomolecules with different fluorescence labels. Both methods can be applied to live cells and, therefore, can be used to address a variety of unsolved questions in cell biology. Applications of FCCS with autofluorescent proteins (AFPs) have been hampered so far by cross talk between the detector channels due to the large spectral overlap of the fluorophores. Here we present a new method that combines advantages of these techniques to analyze binding behavior of proteins in live cells. To achieve this, we have used dual color excitation of a common pair of AFPs, ECFP and EYFP, being discriminated in excitation rather than in emission. This is made possible by pulsed excitation and detection on a shorter timescale compared to the average residence time of particles in the FCS volume element. By this technique we were able to eliminate cross talk in the detector channels and obtain an undisturbed cross correlation signal. The setup was tested with ECFP/EYFP lysates as well as chimeras as negative and positive controls and demonstrated to work in live HeLa cells coexpressing the two fusion proteins ECFP-connexin and EYFP-connexin.

Bacterial Proteins↗

PubMed2004

Chromosomal mapping and zygosity check of transgenes based on flanking genome sequences determined by genomic walking.

Transgenes can affect transgenic mice via transgene expression or via the so-called positional effect. DNA sequences can be localized in chromosomes using recently established mouse genomic databases. In this study, we describe a chromosomal mapping method that uses the genomic walking technique to analyze genomic sequences that flank transgenes, in combination with mouse genome database searches. Genomic DNA was collected from two transgenic mouse lines harboring pCAGGS-based transgenes, and adaptor-ligated, enzyme restricted genomic libraries for each mouse line were constructed. Flanking sequences were determined by sequencing amplicons obtained by PCR amplification of genomic libraries with transgene-specific and adaptor primers. The insertion positions of the transgenes were located by BLAST searches of the Ensembl genome database using the flanking sequences of the transgenes, and the transgenes of the two transgenic mouse lines were mapped onto chromosomes 11 and 3. In addition, flanking sequence information was used to construct flanking primers for a zygosity check. The zygosity (homozygous transgenic, hemizygous transgenic and non-transgenic) of animals could be identified by differential band formation in PCR analyses with the flanking primers. These methods should prove useful for genetic quality control of transgenic animals, even though the mode of transgene integration and the specificity of flanking sequences needs to be taken into account.

5' Flanking Region↗

PubMed1999

Exploration of the structural features defining the conduction properties of a synthetic ion channel.

The finite-difference Poisson-Boltzmann methodology was applied to a series of parallel, alpha-helical bundle models of the designed ion channel peptide Ac-(LSSLLSL)3-CONH2. This method is able to fully describe the current-voltage curves for this channel and quantitatively explains their cation selectivity and rectification. We examined a series of energy-minimized models representing different aggregation states, side-chain rotamers, and helical rotations, as well as an ensemble of structures from a molecular dynamics trajectory. Potential energies were computed for single, permeating K+ and Cl- ions at a series of positions along a central pathway through the models. A variable-electric-field Nernst-Planck electrodiffusion model was used, with two adjustable parameters representing the diffusion coefficients of K+ and Cl- to scale the individual ion current magnitudes. The ability of a given DelPhi potential profile to fit the experimental data depended strongly on the magnitude of the desolvation of the permeating ion. Below a pore radius of 3.8 A, the predicted profiles showed large energy barriers, and the experimental data could be fit only with unrealistically high values for the K+ and Cl- diffusion coefficients. For pore radii above 3.8 A, the desolvation energies were 2kT or less. The electrostatic calculations were sensitive to positioning of the Ser side chains, with the best fits associated with maximum exposure of the Ser side-chain hydroxyls to the pore. The backbone component was shown to be the major source of asymmetry in the DelPhi potential profiles. Only two of the energy-minimized structures were able to explain the experimental data, whereas an average of the dynamics structures gave excellent agreement with experimental results. Thus this method provides a promising approach to prediction of current-voltage curves from three-dimensional structures of ion channel proteins.

Cations↗

PubMed2001

Human- and model-observer performance in ramp-spectrum noise: effects of regularization and object variability.

We consider detection of a nodule signal profile in noisy images meant to roughly simulate the statistical properties of tomographic image reconstructions in nuclear medicine. The images have two sources of variability arising from quantum noise from the imaging process and anatomical variability in the ensemble of objects being imaged. Both of these sources of variability are simulated by a stationary Gaussian random process. Sample images from this process are generated by filtering white-noise images. Human-observer performance in several signal-known-exactly detection tasks is evaluated through psychophysical studies by using the two-alternative forced-choice method. The tasks considered investigate parameters of the images that influence both the signal profile and pixel-to-pixel correlations in the images. The effect of low-pass filtering is investigated as an approximation to regularization implemented by image-reconstruction algorithms. The relative magnitudes of the quantum and the anatomical variability are investigated as an approximation to the effects of exposure time. Finally, we study the effect of the anatomical correlations in the form of an anatomical slope as an approximation to the effects of different tissue types. Human-observer performance is compared with the performance of a number of model observers computed directly from the ensemble statistics of the images used in the experiments for the purpose of finding predictive models. The model observers investigated include a number of nonprewhitening observers, the Hotelling observer (which is equivalent to the ideal observer for these studies), and six implementations of channelized-Hotelling observers. The human observers demonstrate large effects across the experimental parameters investigated. In the regularization study, performance exhibits a mild peak at intermediate levels of regularization before degrading at higher levels. The exposure-time study shows that human observers are able to detect ever more subtle lesions at increased exposure times. The anatomical slope study shows that human-observer performance degrades as anatomical variability extends into higher spatial frequencies. Of the observers tested, the channelized-Hotelling observers best capture the features of the human data.

Artifacts↗

PubMed2000

Parallel excluded volume tempering for polymer melts.

We have developed a technique to accelerate the acquisition of effectively uncorrelated configurations for off-lattice models of dense polymer melts that makes use of both parallel tempering and large-scale Monte Carlo moves. The method is based upon simulating a set of systems in parallel, each of which has a slightly different repulsive core potential, such that a thermodynamic path from full excluded volume to an ideal gas of random walks is generated. While each system is run with standard stochastic dynamics, resulting in an NVT ensemble, we implement the parallel tempering through stochastic swaps between the configurations of adjacent potentials, and the large-scale Monte Carlo moves through attempted pivot and translation moves that reach a realistic acceptance probability as the limit of the ideal gas of random walks is approached. Compared to pure stochastic dynamics, this results in an increased efficiency even for a system of chains as short as N=60 monomers, however at this chain length the large-scale Monte Carlo moves were ineffective. For even longer chains, the speedup becomes substantial, as observed from preliminary data for N=200. We also compare our scheme to the end bridging algorithm of Theodorou et al. For N=60, end bridging must allow a polydispersity of more than 10% in order to relax the end-to-end vector more quickly than our method. The comparison is, however, hampered by the fact that the end-to-end vector becomes a somewhat artificial quantity when one implements end bridging, and is perhaps no longer the slowest dynamic variable.

Algorithms↗

PubMed2004

Discerning the structure and energy of multiple transition states in protein folding using psi-analysis.

We quantify the degree to which folding occurs along a complex landscape with structurally distinct pathways using psi-analysis in combination with a protein engineering method that identifies native, non-covalent polypeptide interactions and their relative populations at the rate-limiting step. By probing the proximity of two specific partners, this method is extremely well-suited for comparison to theoretical simulations. Using ubiquitin as a model system, we detect individual pathways with site-resolved resolution, demonstrating that the protein folds through a native-like transition state ensemble with a common nucleus that contains heterogeneous features on its periphery. The consensus transition state topology has part of the major helix docked against four properly aligned beta-strands. However, structural heterogeneity exists in the transition state ensemble, wherein peripheral regions are differentially populated according to their relative stability. Pathway diversity reflects the variable order of formation of these peripheral elements, which radiate outward from the common nucleus. These results, which show only moderate agreement with traditional mutational phi-analysis, provide an extraordinarily detailed and quantitative description of protein folding.

Amino Acid Sequence↗

PubMed2000

Stability and cooperativity of individual tertiary contacts in RNA revealed through chemical denaturation.

For proteins, understanding tertiary interactions involved in local versus global unfolding has become increasingly important for understanding the nature of the native state ensemble, the mechanisms of unfolding, and the stability of both the native and intermediate states in folding. In this work we have addressed related questions with respect to RNA structure by combining chemical denaturation and hydroxyl radical footprinting methods. We have determined unfolding isotherms for each of 26 discrete sites of protection located throughout the Tetrahymena thermophila group I ribozyme. The cooperativity of folding, m-value, and the free energy, DeltaG degrees N-U, associated with formation of each tertiary contact was determined by analysis of the isotherms. The DeltaG degrees N-U values measured in this study vary from 1.7 +/- 0.2 to 7. 6 +/- 1.2 kcal mol-1. Thus, the stability of these discrete tertiary contacts vary by almost 104. In addition, an intradomain contact and three interdomain contacts show high cooperativity (m-values of 1.1 +/- 0.2 to 1.7 +/- 0.3 kcal mol-1 M-1) indicating that these contacts exhibit global cooperatively in their folding behavior. This new approach to examining RNA stability provides an exciting comparison to our understanding of protein structure and folding mechanisms.

Allosteric Site↗

PubMed2026

ViralQC: a tool for assessing completeness and contamination of predicted viral contigs.

MOTIVATION: Viruses represent the most abundant biological entities on Earth, playing vital roles in diverse ecosystems. Cataloging viruses across various environments is essential for understanding their properties and functions. Metagenomic sequencing has emerged as the most comprehensive method for virus discovery. However, distinguishing viral sequences from the vast background of microbial organisms in metagenomic data remains a significant challenge. Existing tools experience varying degrees of false positive rates due to noise in sequencing and assembly, and the integration of proviruses into microbial genomes. This highlights the urgent need for an accurate and efficient method to evaluate the quality of viral contigs. RESULTS: To address these challenges, we introduce ViralQC, a tool designed to assess the quality of viral contigs or bins. ViralQC identifies microbial contamination within putative viral sequences using an ensemble framework powered by DNA and protein foundation models and estimates completeness by analyzing protein organization. We evaluated ViralQC on multiple datasets and compared its performance against the state-of-the-art tool, CheckV. Leveraging both DNA and protein foundation models, ViralQC achieves higher sensitivity on contamination detection for contigs longer than 10 kbp while maintaining comparable accuracy. Additionally, ViralQC delivers more accurate estimation on contigs with completeness > 50%. AVAILABILITY: The source code of ViralQC is available via: https://github.com/ChengPENG-wolf/ViralQC.

Software↗

PubMed2005

Towards complete descriptions of the free-energy landscapes of proteins.

In recent years increasingly detailed information about the structures and dynamics of protein molecules has been obtained by innovative applications of experimental techniques, in particular nuclear magnetic resonance spectroscopy and protein engineering, and theoretical methods, notably molecular dynamics simulations. In this article we discuss how such approaches can be combined by incorporating a wide range of different types of experimental data as restraints in computer simulations to provide unprecedented detail about the ensembles of structures that describe proteins in a wide variety of states from the native structure to highly unfolded species. Knowledge of these ensembles is beginning to enable the complete free-energy landscapes of individual proteins to be defined at atomic resolution. This strategy has provided new insights into the mechanism by which proteins are able to fold into their native states, or by which they fail to do so and give rise to harmful aggregates that are associated with a wide range of debilitating human diseases.

Computer Simulation↗

PubMed2004

ESTGenes: alternative splicing from ESTs in Ensembl.

We describe a novel algorithm for deriving the minimal set of nonredundant transcripts compatible with the splicing structure of a set of ESTs mapped on a genome. Sets of ESTs with compatible splicing are represented by a special type of graph. We describe the algorithms for building the graphs and for deriving the minimal set of transcripts from the graphs that are compatible with the evidence. These algorithms are part of the Ensembl automatic gene annotation system, and its results, using ESTs, are provided at www.ensembl.org as ESTgenes for the mosquito, Caenorhabditis briggsae, C. elegans, zebrafish, human, mouse, and rat genomes. Here we also report on the results of this method applied to the human and mouse genomes.

Alternative Splicing↗