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PubMed2001

A self-consistent knowledge-based approach to protein design.

A simple and very efficient protein design strategy is proposed by developing some recently introduced theoretical tools which have been successfully applied to exactly solvable protein models. The design approach is implemented by using three amino acid classes and it is based on the minimization of an appropriate energy function. For a given native state the results of the design procedure are compared, through a statistical analysis, with the properties of an ensemble of sequences folding in the same conformation. If the success rate is computed on those sites designed with high confidence, it can be as high as 80%. The method is also able to identify key sites for the folding process: results for 2ci2 and barnase are in very good agreement with experimental results.

Amino Acid Sequence↗
PubMed2004

Determination of protein structures consistent with NMR order parameters.

Order parameters obtained from NMR experiments characterize distributions of bond vector orientations. Their interpretation, however, usually requires the assumption of a particular motional model. We propose a multiple-copy simulation method in which the experimental order parameters are used as restraints in conjunction with a standard molecular force field. The latter effectively acts as a sophisticated motional model, allowing ensembles of structures consistent with the experimental order parameters to be determined.

Cell Adhesion Molecules↗
PubMed1991

MRI-PET correlation in three dimensions using a volume-of-interest (VOI) atlas.

Quantitative interpretation of functional images (PET or SPECT) is hampered by poor spatial resolution, low counting statistics, and, for many tracers, low contrast between different brain structures of interest. Furthermore, normal tracer distributions can be severely disrupted by such gross pathologies as stroke, tumor, and dementia. Hence, the complementary anatomical information provided by CT or MRI is essential for accurate and reproducible regional analysis of functional data. We have developed methods for the simultaneous three-dimensional display and analysis of image volumes from MRI and PET. A general algorithm for defining the affine transformation between two equivalent point ensembles has been adapted for the purpose of registering MRI and PET image volumes by means of a simple fiducial arrangement. In addition, we have extended previous MRI-based computerized atlas methodology to three dimensions. The native atlas planes were spaced at 2 mm intervals, sufficient axial sampling to permit the generation of oblique planar sections through the atlas space. This will allow for an infinite number of angulations and axial offsets in two-dimensional region-of-interest (ROI) templates, all derived from the same master three-dimensional volume-of-interest (VOI) atlas and therefore maintaining topographical consistency throughout. These ROI templates may be selected to match the image orientation for conventional two-dimensional segmentation and data extraction.

Adult↗
PubMed2005

A potential from quantum chemistry for thermodynamic property predictions for methanethiol.

An ab initio potential for methanethiol is determined by computing quantum-chemical interaction energies for a range of orientations and center-of-mass separation distances. These energies are initially fitted to a pairwise-additive, site-site Morse-C6 intermolecular potential. Additional interaction energies were then calculated at separation distances determined to be important from the angle-averaged Mayer f function calculated with the initial potential. This expanded set of interaction energies is then fitted using Boltzmann-type weighting to obtain the final intermolecular potential. Although there are some discrepancies in the fit for a particular type of orientation, the phase behavior calculated from Gibbs ensemble Monte Carlo simulations using this final potential is in very good agreement with experimental data. The prescription used here for obtaining the optimum potential from quantum-chemical methods should be applicable to other systems.

Journal Article↗
PubMed2001

The effect of cooling on muscle co-ordination in spasticity: assessment with the repetitive movement test.

PURPOSE: Cooling muscles might produce a temporary reduction of spasticity. This study investigated muscle co-ordination in spasticity under the influence of cooling. METHODS: A repetitive movement (RM-) test of the ankle was used, while measuring the angle and surface-electromyography (EMG) of the m. tibialis anterior and m. triceps surae. Ensemble averaging provided quantified measures of muscle activation. Sixteen patients with spasticity in their lower extremity due to stroke or spinal cord injury participated in the study. Physical examination and the RM-test was done before and after cooling the m. triceps surae for 20 minutes by coldpacks. RESULTS: The results show that Achilles hyperreflexia and clonus were abolished in all, and all but one patient, respectively. The EMG of the m. triceps surae, acting as a prime mover, was increased (p = 0.028). However, this improved muscle co-ordination resulted in just a slightly increased active range of motion (less than 2 degrees at p = 0.049). CONCLUSION: Apparently, the increase in excitability of the alpha motoneuron pool in voluntary movements of patients with spasticity is not followed by an improvement in the ability to move.

Ankle Joint↗
PubMed2005

Classification ensembles for unbalanced class sizes in predictive toxicology.

This paper investigates the effects of the ratio of positive-to-negative samples on the sensitivity, specificity, and concordance. When the class sizes in the training samples are not equal, the classification rule derived will favor the majority class and result in a low sensitivity on the minority class prediction. We propose an ensemble classification approach to adjust for differential class sizes in a binary classifier system. An ensemble classifier consists of a set of base classifiers; its prediction rule is based on a summary measure of individual classifications by the base classifiers. Two re-sampling methods, augmentation and abatement, are proposed to generate different bootstrap samples of equal class size to build the base classifiers. The augmentation method balances the two class sizes by bootstrapping additional samples from the minority class, whereas the abatement method balances the two class sizes by sampling only a subset of samples from the majority class. The proposed procedure is applied to a data set to predict estrogen receptor binding activity and to a data set to predict animal liver carcinogenicity using SAR (structure-activity relationship) models as base classifiers. The abatement method appears to perform well in balancing sensitivity and specificity.

Discriminant Analysis↗
PubMed2006

Condensation of N interacting bosons: a hybrid approach to condensate fluctuations.

We present a new method of calculating the distribution function and fluctuations for a Bose-Einstein condensate (BEC) of N interacting atoms. The present formulation combines our previous master equation and canonical ensemble quasiparticle techniques. It is applicable both for ideal and interacting Bogoliubov BEC and yields remarkable accuracy at all temperatures. For the interacting gas of 200 bosons in a box we plot the temperature dependence of the first four central moments of the condensate particle number and compare the results with the ideal gas. For the interacting mesoscopic BEC, as with the ideal gas, we find a smooth transition for the condensate particle number as we pass through the critical temperature.

Journal Article↗
PubMed2003

Sheldrick's 1.2 A rule and beyond.

An average profile of squared normalized structure factors as a function of resolution, /E/2>(d*), calculated from a large ensemble of high-resolution protein models, is presented. An interpretation is given that provides a structural explanation for Sheldrick's 1.2 A rule for the applicability of direct methods. The implications for the potential effectiveness of extended direct methods, incorporating stereochemical knowledge, are discussed.

Algorithms↗
PubMed1997

Applications of high-energy synchrotron radiation for structural studies of polycrystalline materials.

The large penetration power of high-energy X-rays (>60 keV) raises interesting prospects for new types of structural characterizations of polycrystalline materials. It becomes possible in a non-destructive manner to perform local studies, within the bulk of the material, of the fundamental materials physics properties: grain orientations, strain, dislocation densities etc. In favourable cases these properties may be mapped in three dimensions with a spatial resolution that matches the dimensions of the individual grains. Imbedded volumes and interfaces become accessible. Moreover, the high energies allow better in-situ studies of samples in complicated environments (industrial process optimization). General techniques for research in this energy range have been developed using broad-band angle-dispersive methods, on-line two-dimensional detectors and conical slits. Characterizations have been made at the level of the individual grains and grain boundaries as well as on ensembles of grains. The spatial resolution is presently of the order of 10-100 micom. Four examples of applications are presented along with an outlook.

Journal Article↗
PubMed2006

A random search methodology for examining parametric uncertainty in water quality models.

The advent of the modern high-speed digital computer has tremendously enhanced the utility of Monte Carlo methods for evaluating complex environmental simulation models. In particular, random searching is becoming popular, as thousands of model runs can now be executed quickly and with minimal effort. Indeed, the issues of computational burden and inefficiency, hitherto the bane of random searching, are now receding. This paper presents one such method, uniform covering by probabilistic rejection (UCPR), which combines a pure random search with a probabilistic rejection algorithm that significantly enhances its efficiency. Using nearest-neighbor distances, an ensemble of points in a predefined parameter sampling domain migrates to locate and define a final distribution of optimal parameter vectors, thus providing a realistic depiction of parameter uncertainty. In a prototypical case study of the Oconee River (Georgia, USA), UCPR and regionalized sensitivity analysis, are employed for identifying the parameters of sediment-transport-associated nutrient dynamics, a dynamic river water quality model. Results indicate the existence of a complex interactive parameter structure, evidenced by multiple sets of optimal points widely dispersed over a broad domain of feasible parameter values.

Algorithms↗
PubMed2001

Hydraulic properties of individual xylem vessels of Fraxinus americana.

Studies of the hydraulic properties of xylem vessels have been limited to measurements of whole plant or whole stem segments. This approach allows the longitudinal transport properties of the ensemble of vessels within a stem to be determined, but provides little information on radial transport. Here the xylem of Fraxinus americana L. has been examined using a new method that allows the transport properties of individual vessels to be examined. One goal of this study was to quantify transport parameters relevant to embolism repair. The longitudinal conductivity of vessel segments open at both ends (i.e. no end walls) agreed with values predicted by the Poiseuille equation. Radial specific conductance (conductance per unit area) was approximately six orders of magnitude lower than the longitudinal conductance of the vessel segment normalized by the cross-sectional area of the vessel lumen. There was a step increase in the radial specific conductance of previously gas-filled vessels when the delivery pressure exceeded 0.4 MPa. This is consistent with the idea that positive pressure, required for embolism repair, can be compartmentalized within a vessel if the bordered pit chambers are gas-filled. The diffusion coefficient for the movement of gas from a pressurized air-filled vessel was of the same order of magnitude as that for air diffusing through water (1.95 e(-9) m(2) s(-1)). Estimates of the time needed to displace all of the gas from an air-filled vessel were in the order of 20 min, suggesting that gas removal may not be a major limitation in embolism repair.

Biological Transport↗
PubMed2002

Addition of missing loops and domains to protein models by x-ray solution scattering.

Inherent flexibility and conformational heterogeneity in proteins can often result in the absence of loops and even entire domains in structures determined by x-ray crystallographic or NMR methods. X-ray solution scattering offers the possibility of obtaining complementary information regarding the structures of these disordered protein regions. Methods are presented for adding missing loops or domains by fixing a known structure and building the unknown regions to fit the experimental scattering data obtained from the entire particle. Simulated annealing was used to minimize a scoring function containing the discrepancy between the experimental and calculated patterns and the relevant penalty terms. In low-resolution models where interface location between known and unknown parts is not available, a gas of dummy residues represents the missing domain. In high-resolution models where the interface is known, loops or domains are represented as interconnected chains (or ensembles of residues with spring forces between the C(alpha) atoms), attached to known position(s) in the available structure. Native-like folds of missing fragments can be obtained by imposing residue-specific constraints. After validation in simulated examples, the methods have been applied to add missing loops or domains to several proteins where partial structures were available.

Algorithms↗
PubMed1989

Selective elimination of interactions: a method for assessing thermodynamic contributions to ligand binding with application to rhinovirus antivirals.

A new method for evaluating the free energy of various physical interactions, such as hydrogen-bond, electrostatic, or van der Waals interactions, is presented. Rather than destroying or creating whole groups, selective (pairwise) interactions are eliminated from the total potential energy and the energy difference with the fully interacting system is evaluated. The exponential ensemble average of such an energy difference is then directly related to the corresponding free energy difference. This procedure is then applied to a rather large protein-ligand system involving the coat proteins of a human rhinovirus and an antiviral ligand. The results seem to indicate that a particular bent hydrogen bond between the ligand and protein system may not be favorable for binding. The method presented gives an estimate of the hydrogen bond free energy contribution with an available trajectory that was previously computed without the expenditure of sizeable computational resources such as recomputing a trajectory. This procedure is effective and efficient for computing the free energy for a given type of physical interaction. It can be used for calculating the binding energy differences for various interactions which can be used to guide the search for isosoluble synthetic targets.

Antiviral Agents↗
PubMed1997

Exploring the fitness landscapes of lattice proteins.

We present methods to investigate the sequence to structure relation for proteins. We use random structures of HP-type lattice models as a coarse grained model to study generic properties of biopolymers. To circumvent the computational limitations imposed by most lattice protein folding algorithms we apply a simple and fast deterministic approximation algorithm with a tunable accuracy. We investigate ensemble properties such as the conditional probability to find structures with a certain similarity at a given distance of the underlying sequence for various alphabets. Our results suggest that the structure landscapes for lattice proteins are generally very rugged, while larger alphabets fine tune the folding process and smoothen the map. This implies a simplification for evolutionary strategies. The applied methods appear to be helpful in the study of the complex interplay between folding strategies, energy functions and alphabets. Possible implications to the investigation of evolutionary strategies or the optimization of biopolymers are discussed.

Algorithms↗
PubMed2004

Conformational heterogeneity of an equilibrium folding intermediate quantified and mapped by scanning mutagenesis.

It is challenging to experimentally define an energy landscape for protein folding that comprises multiple partially unfolded states. Experimental results are often ambiguous as to whether a non-native state is conformationally homogeneous. Here, we tested an approach combining systematic mutagenesis and a Brønsted-like analysis to reveal and quantify conformational heterogeneity of folding intermediate states. Using this method, we resolved an otherwise apparently homogeneous equilibrium folding intermediate of Borrelia burgdorferi OspA into two conformationally distinct species and determined their relative populations. Furthermore, we mapped the structural differences between these intermediate species, which are consistent with the non-native species that we previously proposed based on native-state hydrogen exchange studies. When treated as a single state, the intermediate ensemble exhibited fractional Phi-values for mutations and Hammond-type behaviors that are often observed for folding transition states. We found that a change in relative population of the two species within the intermediate ensemble explains these properties well, suggesting that fractional Phi-values and Hammond-type behaviors exhibited by folding intermediates and transition states may arise more often from conformational heterogeneity than from a single partial structure. Our results are consistent with the presence of multiple minima in a rugged energy landscape predicted from theoretical studies. The method described here provides a promising means to probe a complex folding energy landscape.

Antigens, Surface↗
PubMed2001

Single-event-related potential analysis by means of fragmentary decomposition.

A recently developed fragmentary decomposition method is employed to analyse single-trial event-related potentials (ERPs), thereby extending the traditional method of averaging. Using a conventional auditory oddball paradigm with 40 target stimuli, single-trial ERPs in 40 normal subjects were analysed for midline scalp (Fz, Cz and Pz) recording sites. The normalization effect, reported in our previous study of eye blink EMGs and proposed to be a characteristic property of a wide class of non-stationary physiological processes, was found to apply to these single-trial ERPs. Fragmentary decomposition of single-trial ERPs may be regarded as re-statement of the normalization effect. This allows both pre-stimulus EEGs and post-stimulus ERPs to be regarded as overlapping generic mass potentials (GMPs), with a characteristic Gaussian amplitude spectrum. On theoretical and empirical grounds we uniquely deduce a model GMP using an introduced d" function, and physically support it by the resting and transient conditions. The model takes into account the shape of the component, which suggests a simple relationship between the peak latency and the time of the component onset. Given that GMPs may be manipulated and sorted out, we present principles of the fragmentary synthesis, i.e. probabilistic ERP reconstructions on the basis of individual and ensemble properties of its identified components. Summarizing the component quantification in the form of the dynamic model provides for the first time the opportunity to quantify all significant components in single-trial ERPs. This method of single-trial analysis opens up new possibilities of exploring the dynamical ERP changes within a recording trial, particularly in late component "cognitive" paradigms.

Adult↗
PubMed1995

Optimal filtering and quality control of the signal-averaged ECG. High-fidelity 1-minute recordings.

BACKGROUND: The clinical performance of the signal-averaged ECG (SAECG) for prediction of ventricular tachycardia (VT) depends on its quality, or final noise level. However, signal averaging is a statistical estimation procedure that is time-consuming and vulnerable to noise-induced error. The optimally filtered SAECG is proposed as a simple, quality-assured procedure requiring only 1 minute of data. METHODS AND RESULTS: The optimally filtered SAECG is based on measures of signal variance and time-frequency representations. Forty subjects were studied to compare a 0.3-microV root-mean-square (RMS) noise endpoint SAECG with an optimally filtered 64-beat ensemble. Eight SAECGs were computed with noise endpoints of 1.0-through 0.3-microV RMS. Noise measurements were also made directly from the filtered SAECG. From these and previously published data, sensitivity was predicted as a function of noise endpoint. Measured QRS parameters and final noise were highly similar between the optimally filtered SAECG and the 0.3-microV RMS noise endpoint SAECG. CONCLUSIONS: The optimally filtered 64-beat SAECG achieves a performance (equivalent noise reduction, signal definition, and mathematically predicted sensitivity for VT) similar to a 0.3-microV RMS noise endpoint average. Testing in a large clinical database is required to validate the method for routine clinical use. SAECGs terminated by use of different noise measurement techniques are not directly comparable because of measurement technique dependence. However, a formula is presented for comparison of statistics between studies that have used the most popular noise measurement techniques.

Electrocardiography↗
PubMed2004

An epsilon-margin nonlinear classifier based on fuzzy if-then rules.

This paper introduces a new classifier design methods that are based on a modification of the classical Ho-Kashyap procedure. First, it proposes a method to design a linear classifier using the absolute loss rather than the squared loss that results in a better approximation of the misclassification error and robustness of outliers. Additionally, easy control of the generalization ability is obtained by minimization of the Vapnik-Chervonenkis dimension. Next, an extension to a nonlinear classifier by an ensemble averaging technique is presented. Each classifier is represented by a fuzzy if-then rule in the Takagi-Sugeno-Kang form. Two approaches to the estimation of parameters value are used: local, where each of the if-then rule parameters are determined independently and global where all rules are obtained simultaneously. Finally, examples are given to demonstrate the validity of the introduced methods.

Journal Article↗