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PubMed2006

Quantum Monte Carlo simulation in the canonical ensemble at finite temperature.

A quantum Monte Carlo method with a nonlocal update scheme is presented. The method is based on a path-integral decomposition and a worm operator which is local in imaginary time. It generates states with a fixed number of particles and respects other exact symmetries. Observables like the equal-time Green's function can be evaluated in an efficient way. To demonstrate the versatility of the method, results for the one-dimensional Bose-Hubbard model and a nuclear pairing model are presented. Within the context of the Bose-Hubbard model the efficiency of the algorithm is discussed.

Journal Article↗

PubMed2003

Long-lived memory for mesoscopic quantum bits.

We describe a technique to create long-lived quantum memory for quantum bits in mesoscopic systems. Specifically we show that electronic spin coherence can be reversibly mapped onto the collective state of the surrounding nuclei. The coherent transfer can be efficient and fast and it can be used, when combined with standard resonance techniques, to reversibly store coherent superpositions on the time scale of seconds. This method can also allow for "engineering" entangled states of nuclear ensembles and efficiently manipulating the stored states. We investigate the feasibility of this method through a detailed analysis of the coherence properties of the system.

Journal Article↗

PubMed2006

SimFold energy function for de novo protein structure prediction: consensus with Rosetta.

Predicting protein tertiary structures by in silico folding is still very difficult for proteins that have new folds. Here, we developed a coarse-grained energy function, SimFold, for de novo structure prediction, performed a benchmark test of prediction with fragment assembly simulations for 38 test proteins, and proposed consensus prediction with Rosetta. The SimFold energy consists of many terms that take into account solvent-induced effects on the basis of physicochemical consideration. In the benchmark test, SimFold succeeded in predicting native structures within 6.5 A for 12 of 38 proteins; this success rate was the same as that by the publicly available version of Rosetta (ab initio version 1.2) run with default parameters. We investigated which energy terms in SimFold contribute to structure prediction performance, finding that the hydrophobic interaction is the most crucial for the prediction, whereas other sequence-specific terms have weak but positive roles. In the benchmark, well-predicted proteins by SimFold and by Rosetta were not the same for 5 of 12 proteins, which led us to introduce consensus prediction. With combined decoys, we succeeded in prediction for 16 proteins, four more than SimFold or Rosetta separately. For each of 38 proteins, structural ensembles generated by SimFold and by Rosetta were qualitatively compared by mapping sampled structural space onto two dimensions. For proteins of which one of the two methods succeeded and the other failed in prediction, the former had a less scattered ensemble located around the native. For proteins of which both methods succeeded in prediction, often two ensembles were mixed up.

Alanine↗

PubMed2001

Multiple protein folding nuclei and the transition state ensemble in two-state proteins.

Using exhaustive simulations of lattice models with side-chains, we show that optimized two-state folders reach the native state by a nucleation-collapse mechanism with multiple folding nuclei (MFN). For both the full model and the Go version, there are certain contacts that on an average participate in the critical nuclei with higher probability than the others. The high- (> or = 0.5) probability contacts are largely determined by the structure of the native state. Comparison of the results for the full sequence and the Go model shows that non-native interactions compromise the degree of cooperativity and stability of the native state. From an extremely detailed analysis of the folding kinetics, we find that non-native interactions are present in the folding nuclei. The folding times decrease if the non-native interactions in the folding nuclei are made neutral or repulsive. Using cluster analysis and making no prior assumption about reaction coordinate, we show that both full and Go models have three distinct transition states that give a structural description for the MFN. In the transition states, on an average, about two-thirds of the sequence is structured, whereas the rest is disordered, reminiscent of the polarized transition state in the SH3 domain. Our studies show that Go models cannot describe the transition state characteristics of two-state folders at the molecular level. As a byproduct of our investigations, we establish that our method of computing the transition state ensemble is numerically equivalent to the technique based on the stochastic separatrix, which also does not require a priori knowledge of the folding reaction coordinate.

Algorithms↗

PubMed1997

Molecular docking to ensembles of protein structures.

Until recently, applications of molecular docking assumed that the macromolecular receptor exists in a single, rigid conformation. However, structural studies involving different ligands bound to the same target biomolecule frequently reveal modest but significant conformational changes in the target. In this paper, two related methods for molecular docking are described that utilize information on conformational variability from ensembles of experimental receptor structures. One method combines the information into an "energy-weighted average" of the interaction energy between a ligand and each receptor structure. The other method performs the averaging on a structural level, producing a "geometry-weighted average" of the inter-molecular force field score used in DOCK 3.5. Both methods have been applied in docking small molecules to ensembles of crystal and solution structures, and we show that experimentally determined binding orientations and computed energies of known ligands can be reproduced accurately. The use of composite grids, when conformationally different protein structures are available, yields an improvement in computational speed for database searches in proportion to the number of structures.

Computer Simulation↗

PubMed2004

Prediction of postoperative morbidity after lung resection using an artificial neural network ensemble.

OBJECTIVE: To propose an ensemble model of artificial neural networks (ANNs) to predict cardio-respiratory morbidity after pulmonary resection for non-small cell lung cancer (NSCLC). METHODS: Prospective clinical study was based on 489 NSCLC operated cases. An artificial neural network ensemble was developed using a training set of 348 patients undergoing lung resection between 1994 and 1999. Predictive variables used were: sex of the patient, age, body mass index, ischemic heart disease, cardiac arrhythmia, diabetes mellitus, induction chemotherapy, extent of resection, chest wall resection, perioperative blood transfusion, tumour staging, forced expiratory volume in 1s percent (FEV(1)%), and predicted postoperative FEV(1)% (ppoFEV(1)%). The analysed outcome was the occurrence of postoperative cardio-respiratory complications prospectively recorded and codified. The artificial neural network ensemble consists of 100 backpropagation networks combined via a simple averaging method. The probabilities of complication calculated by ensemble model were obtained to the actual occurrence of complications in 141 cases operated on between January 2000 and December 2001 and a receiver operating characteristic (ROC) curve for this method was constructed. RESULTS: The prevalence of cardio-respiratory morbidity was 0.25 in the training and 0.30 in the validation series. The accuracy for morbidity prediction (area under the ROC curve) was 0.98 by the ensemble model. CONCLUSION: In this series an artificial neural network ensemble offered a high performance to predict postoperative cardio-respiratory morbidity.

Aged↗

PubMed2004

Computational methods for generating models of denatured and partially folded proteins.

Partially folded and denatured proteins can give important insights into protein folding, misfolding, and aggregation. Such non-native states of proteins are however very difficult to characterise in detail as they are dynamic, heterogeneous systems comprising of ensembles of interconverting conformers. This article describes methods that produce models for non-native proteins in atomic detail. A variety of molecular dynamics based protocols are discussed together with some recent procedures that include restraints from experimental data. These models provide an important framework for interpreting experimental data from studies of non-native states using nuclear magnetic resonance spectroscopy, fluorescence, circular dichroism, and small angle scattering techniques.

Animals↗

PubMed2000

The Structure of Adsorbed CO(2) in Slitlike Micropores at Low and High Temperature and the Resulting Micropore Size Distribution Based on GCMC Simulations.

The Monte Carlo method is used in its grand ensemble variant in combination with CO(2) experimental isotherm data at low (195.5 K) and high temperatures (at 298 and 308 K, i.e., slightly below and above the CO(2) critical temperature, respectively) to characterize microporous carbons and obtain the corresponding pore size distribution (PSD). Specifically, the CO(2) density inside a single, slit-shaped, graphitic pore of given width is found on the basis of grand canonical Monte Carlo (GCMC) simulations for a predefined temperature and different relative pressures. The simulation results provide useful insights concerning the densification process in the micropores and the structure of the CO(2) molecules packing in the individual pores as the temperature or pressure changes from 195.5 K to ambient or from very low to 70 bar, respectively. Effects of temperature, pore size, quadrupole interactions, and molecule elongation on the local density profile within the pore are examined and discussed. In an additional step, we determine the optimal PSD for which the best match is obtained between computed and measured CO(2) isotherms. Comparisons are made between the PSDs found for the same carbon sample at low and high temperatures and conclusions are drawn concerning the applicability of the method and the reliability of the resulting micropore size distributions. Copyright 2000 Academic Press.

Journal Article↗

PubMed1995

Minimizing the effect of period determination on the computation of amplitude perturbation in voice.

Current methods of computing amplitude perturbation present in human voices depend upon being able to accurately determine fundamental period. In this paper, two methods of estimating the amplitude perturbation present in human voices, which do not depend on accurate determination of the boundaries between fundamental periods, are described. In both of these methods, amplitude perturbation is computed as the variance of an ensemble of periods calculated after these periods have been aligned in time. In one method, time alignment is accomplished using zero-phase transformation. In the second method, an unconstrained dynamic programming procedure is used. The accuracy of estimating amplitude perturbation by these two methods is evaluated using synthetic and natural voice signals and is also compared with an estimation using zero-padding based time alignment. The unconstrained dynamic programming method is shown to provide accurate estimation of voice amplitude perturbation over a variety of signal conditions.

Female↗

PubMed2002

Discovery of nonpeptide, peptidomimetic peptidase inhibitors that target alternate enzyme active site conformations.

Structure-generating programs provide rational methods to rapidly design novel scaffolds targeting the biologic receptor of choice. Recent research has demonstrated proteins equilibrate between families of conformations (ensembles) for which drug design may target. New methods are currently being developed utilizing structure-generating programs to target alternate enzyme conformations in an attempt to overcome the challenge of developing therapeutically useful molecules. These new methods provide the potential to overcome bioavailability problems encountered with peptide and peptide-like molecules by identifying novel small molecule scaffolds.

Binding Sites↗

PubMedDate not supplied

Global analysis of lymphocyte gene expression: perturbation of H-9 cells by infection with distinct isolates of human immunodeficiency virus--an exposition by multivariate analysis of a host-parasite interface.

AIDS is a progressive disease associated with steady loss of helper T cells and several other functions. As the disease evolves, cytopathogenic human immunodeficiency (HIV) variants of increasing virulence can be isolated from the host. The HIV is an unusually variable genome by virtue of a low replication fidelity. In this report we describe our effort to test the hypothesis that there is a correlation between virus variability and cytopathogenicity, and further, that there is an "impact" of the virus infection on the expression of host cellular genes. To search for such a relationship, we infected H-9 cells (human CD4+ lymphoblastoid cell line) with each of 5 isolates of HIV of distinct origin and cytopathogenicity. To measure the influence of the virus infection on the expression of host cellular genes, shortly after infection, (3 h or 13 h), cells were radiolabeled and the radioactive polypeptides separated by two-dimensional gel electrophoresis. Radiofluorographs were prepared and analyzed to determine relative rates of biosynthesis of cellular polypeptides. To organize the large amounts of data found, cluster analysis and principal component analysis were used to expose the data in formats that allowed a model construction. The rates of biosynthesis of many cellular polypeptides were altered upon viral infection in terms of both enhancements and impairment of biosynthesis. Some of the variation in polypeptide synthesis was isolate-specific, while most alterations were of modest magnitude. There appears to be no "overall effect" associated with infection by a cytopathic variant of the virus. Polypeptides affected by the cytopathic variants were determined as targets for further investigation. The method used promotes the measurement of "ensemble" information that is characteristic of the process and it promotes the creation of models of virus action.

Acquired Immunodeficiency Syndrome↗

PubMed2002

Protein folding in mode space: a collective coordinate approach to structure prediction.

Does the dynamics of a protein encode its structure? Many studies have addressed the inverse of this question-how a three-dimensional structure determines its dynamics-using molecular dynamics simulation, normal mode analysis, and similar methods. Recently we have developed a molecular dynamics (MD) simulation method to impose dynamic properties on ensembles of MD trajectories in the form of restraints on structural diversity in the directions of the principal components of motion of the molecule. In the current work, we investigate if these restraints in combination with a standard MD force field are sufficient to generate native structure in disordered structural ensembles. We present simulations from a series of increasingly disordered structural ensembles obtained by thermal unfolding or randomization of the coordinates of the native structure of two src-homology 3 (SH3) domains. Native structure formation is observed under the sole action of the diversity restraint and the MD force field. We investigate the importance of accuracy of the description of native dynamics. Protein folding is a highly cooperative process. The dynamic restraints may enforce long-range cooperativity and thus speed up the folding from unstructured states. Applications of the restraints to structure refinement and structure prediction are possible.

Animals↗

PubMed1993

Relationship between cardiac output and oxygen uptake at the onset of exercise.

The purpose of the present study was to assess the relationship between the rapidity of increased gas exchange (i.e. oxygen uptake VO2) and increased cardiac output (Qc) during the transient phase following the onset of exercise. Five healthy male subjects performed multiple rest-exercise or light exercise (25 W)-exercise transitions on an electrically braked ergometer at exercise intensities of 50, 75, or 100 W for 6 min, respectively. Each transition was performed at least eight times for each load in random order. The VO2 was obtained by a breath-by-breath method, and Qc was measured by an impedance method during normal breathing, using an ensemble average. On transitions from rest to exercise, VO2 rapidly increased during phase I with time constants of 6.8-7.3 s. The Qc also showed a similar rapid increment with time constants of 6.0-6.8 s with an apparent increase in stroke volume (SV). In this phase I, VO2 increased to about 29.7%-34.1% of the steady-state value and Qc increased to about 58.3%-87.0%. Thereafter, some 20 s after the onset of exercise a mono-exponential increase to steady-state occurred both in VO2 and Qc with time constants of 26.7-32.3 and 23.7-34.4 s, respectively. The insignificant difference between Qc and VO2 time constants in phase I and the abrupt increase in both Qc and SV at the onset of exercise from rest provided further evidence for a "cardiodynamic" contribution to VO2 following the onset of exercise from rest.

Adult↗

PubMed2005

UV-vis spectroscopic study directly detecting inorganic phosphorus in urine and our reagent kit.

The determination of inorganic phosphorus in human urine is very important, since it has diagnostic value in some clinical cases. Here we apply a simple, sensitive and direct method to determine inorganic phosphorus in urine. This new ensemble is prepared by adding ytterbium chloride and pyrocatechol violet in a 2:1 molar ratio in an aqueous solution of 10 mM 2-[4-(2-hydroxyethyl)-1-piperazinyl]ethanesulfonic acid buffer at pH 7.0. The addition of the urine sample turned the blue ensemble yellow and altered the UV-vis absorption spectra. The ensemble exhibits excellent selectivity for inorganic phosphorus over other constituents of urine. We validate the accuracy of our method by the standard procedure (molybdenum blue assay for phosphate). The detection results are basically consistent with normal excretion of phosphate. Furthermore, we fabricated a new kind of inorganic phosphorus reagent kit, which enables us to inspect phosphate concentrations of urine with the naked eye. Fit for all kinds of various clinic uses, our reagent kit is a hopeful substitute for the molybdenum reagent kit.

Benzenesulfonates↗

PubMed2006

Revolutions in RNA secondary structure prediction.

RNA structure formation is hierarchical and, therefore, secondary structure, the sum of canonical base-pairs, can generally be predicted without knowledge of the three-dimensional structure. Secondary structure prediction algorithms evolved from predicting a single, lowest free energy structure to their current state where statistics can be determined from the thermodynamic ensemble. This article reviews the free energy minimization technique and the salient revolutions in the dynamic programming algorithm methods for secondary structure prediction. Emphasis is placed on highlighting the recently developed method, which statistically samples structures from the complete Boltzmann ensemble.

Algorithms↗

PubMed2002

Target immunity during Mu DNA transposition. Transpososome assembly and DNA looping enhance MuA-mediated disassembly of the MuB target complex.

The Mu transpososome can distinguish between proximal and distal DNA during the selection of a site for transposition. This phenomenon, termed target immunity, involves MuA-stimulated removal of MuB oligomers from sites near the Mu genome. Using a combination of ensemble and single-molecule fluorescence methods, we show that the MuA tetramer can stably associate with the DNA-bound MuB oligomer and is more efficient than monomeric MuA at stimulating the dissociation of MuB from DNA. In addition, we demonstrate that DNA looping is essential for efficient disassembly of the MuB oligomer. We propose a model in which the MuA tetramer forms a multivalent complex with the MuB oligomer and catalyzes the processive removal of MuB from DNA.

DNA↗

PubMed2002

Single-molecule fluorescence of nucleic acids.

Less than a decade old, single-molecule fluorescence of nucleic acids has rapidly become an important tool in the arsenal of biological probes. A variety of novel approaches to investigate conformational dynamics, catalytic mechanisms, folding pathways and protein-nucleic-acid interactions have recently been devised for nucleic acids using this technique. Combined with biomechanical tools and ensemble measurements, single-molecule fluorescence methods extend our ability to observe and understand biomolecules and complex biological processes.

DNA↗

PubMed1986

The ensemble approach to distance geometry: application to the nicotinic pharmacophore.

We develop an extension of conventional distance geometry techniques that treats two or more molecules as a single "ensemble". This extension can be used to find a common pharmacophore, i.e., the spatial arrangement of essential groups, from a small set of biologically active molecules. The approach can generate, in one step, coordinates for the set of molecules in their "active" conformations such that their essential groups are superimposed. As an example, we show how the nicotinic pharmacophore can be deduced from a set of four nicotinic agonists: nicotine, cytisine, ferruginine methiodide, and muscarone. Three essential groups in each agonist are chosen: the cationic center (A), an electronegative atom (B), and an atom (C) that forms a dipole with B. There is only one pharmacophore possible for the superposition of these essential groups: a triangle with sides 4.8 A (A-B), 4.0 A (A-C), and 1.2 A (B-C). The pharmacophore triangle, which is consistent with previous models in the literature, can also be achieved by the agonist trans-3,3'-bis[(trimethylammonio)methyl]azobenzene and the antagonists strychnine, trimethaphan, and dihydro-beta-erythroidine. An examination of the common volumes of agonists suggests a specific disposition of molecular volume relative to the pharmacophore triangle. We discuss the relative strengths and drawbacks of the ensemble approach vs. other conformational search methods.

Alkaloids↗