Abstract: Disclosed is are methods of generating chemical structures of putative non-peptide inhibitors of biologically-active receptors. The method includes constructing a model of a receptor-ligand complex using empirical three-dimensional data of the receptor-ligand complex. The conformation of the binding site between the receptor and the ligand is then altered to yield novel conformations not exhibited in either the native receptor or the bound receptor. These conformations are then used to generate models of non-peptide chemical structures that are complementary in structure to the altered conformations of the binding site. In this fashion, chemical structures of putative non-peptide inhibitors of the altered conformation are revealed.

Abstract: The invention provides methods for producing high resolution crystals of ribosomes and ribosomal subunits as well as crystals produced by such methods. The invention also provides high resolution structures of ribosomal subunits either alone or in combination with protein synthesis inhibitors. The invention provides methods for identifying ribosome-related ligands and methods for designing ligands with specific ribosome-binding properties as well as ligands that may act as protein synthesis inhibitors. Thus, the methods and compositions of the invention may be used to produce ligands that are designed to specifically kill or inhibit the growth of any target organism.

Abstract: The invention provides methods for producing high resolution crystals of ribosomes and ribosomal subunits as well as crystals produced by such methods. The invention also provides high resolution structures of ribosomal subunits either alone or in combination with protein synthesis inhibitors. The invention provides methods for identifying ribosome-related ligands and methods for designing ligands with specific ribosome-binding properties as well as ligands that may act as protein synthesis inhibitors. Thus, the methods and compositions of the invention may be used to produce ligands that are designed to specifically kill or inhibit the growth of any target organism.

Abstract: A system for characterizing periodic structures on a real time basis is disclosed. A multi-parameter measurement module generates output signals as a function of wavelength or angle of incidence. The output signals are supplied to a parallel processor, which creates an initial theoretical model and calculates the theoretical optical response. The calculated optical response is compared to measured values. Based on the comparison, the model configuration is modified to be closer to the actual measured structure. Thereafter, the complexity of the model is iteratively increased, by dividing the model into layers each having an associated width and height. The model is fit to the data in an iterative manner until a best fit model is obtained which is similar in structure to the periodic structure.

Abstract: The present invention relates to a method of designing compounds able to bind to a molecule of the EGF receptor family and to modulate the activity mediated by the receptor molecule based on the 3-D structure coordinates of the EGF receptor crystal of FIG. 6.

Abstract: The present invention provides methods for producing high resolution crystals of ribosomes and ribosomal subunits as well as the crystals produced by such methods. The x-ray diffraction patterns of the crystals provided by the present invention are of sufficiently high resolution for determining the three-dimensional structure of ribosomes and ribosomal subunits, for identifying ligand binding sites on ribosomes and ribosomal subunits, and for molecular modeling of ligands which interact with ribosomes and ribosomal subunits. The present invention provides methods for identifying ribosome-related ligands and methods for designing ligands with specific ribosome-binding properties. Thus, the methods of the present invention may be used to produce ligands which are designed to kill or inhibit any specific target organism(s).

Abstract: With compounds for drugs, agricultural chemicals, etc., the invention provides a novel method for superposing molecular structures of those compounds.

Abstract: A method for maintaining consistent unit relationships during graphical pharmacological computational model construction is disclosed. A graphical user interface is presented through which a user may place and connect objects representing pharmacokinetic and pharmacodynamic elements. The user may specify units definitions for variables and constants using unit expressions. As the objects are converted into an internal format representing the statements of the corresponding computational model, the unit expressions are included in this internal format as multidimensional data type information. This multidimensional data type information is regularly and automatically propagated for each statement in the internal format to identify inconsistent units. When such inconsistent units are identified, a warning message is generated to notify the user, substantially immediately after the inconsistent units are created.

Abstract: The present invention relates to the three dimensional structure of human collagenase 3 (MMP-13), as well as to (i) methods of using the MMP-13 structure to rationally design or identify compounds or molecules that inhibit or activate MMP-13 activity, and (ii) compounds identified using said methods.

Abstract: A maximum-likelihood method for improves an electron density map of an experimental crystal structure. A likelihood of a set of structure factors {Fh} is formed for the experimental crystal structure as (1) the likelihood of having obtained an observed set of structure factors {FhOBS} if structure factor set {Fh} was correct, and (2) the likelihood that an electron density map resulting from {Fh} is consistent with selected prior knowledge about the experimental crystal structure. The set of structure factors {Fh} is then adjusted to maximize the likelihood of {Fh} for the experimental crystal structure. An improved electron density map is constructed with the maximized structure factors.

Abstract: A method and system for calibrating molecular arrays to a reference molecular array, and for subsequently calibrating the molecular arrays to maintain a constant signal-intensity-to-label-concentration ratio. In the first step of the two-step calibration method, a reference array coated with the fluorophore or chromophore used to label probe molecules is employed, while in the second step of the two-step method, a reference array coated with a stable dye is employed.

Abstract: The invention provides an X-ray crystal structure of the 30S ribosome, obtained from Thermus thermophilus 30S subunit, having a tetragonal space group P41212 with unit cell dimensions of a=401.4±4.0 ?, b=401.4±4.0 ?, c=175.9±5.0 ?. An advantageous feature of the structure is that it diffracts beyond 3 ? resolution. The invention also provides a crystal of 30S having the three dimensional atomic coordinates of the 30S ribosome, the coordinates being provided in Tables 1A and 1B. The data may be used for the rational design and modelling of inhibitors for the 30S ribosome, which have potential use as antibiotics.

Abstract: The invention describes a process for determining a biological state through the discovery and analysis of hidden or non-obvious, discriminatory biological data patterns. The biological data can be from health data, clinical data, or from a biological sample, (e.g., a biological sample from a human, e.g., serum, blood, saliva, plasma, nipple aspirants, synovial fluids, cerebrospinal fluids, sweat, urine, fecal matter, tears, bronchial lavage, swabbings, needle aspirantas, semen, vaginal fluids, pre-ejaculate.), etc. which is analyzed to determine the biological state of the donor. The biological state can be a pathologic diagnosis, toxicity state, efficacy of a drug, prognosis of a disease, etc. Specifically, the invention concerns processes that discover hidden discriminatory biological data patterns (e.g., patterns of protein expression in a serum sample that classify the biological state of an organ) that describe biological states.

Abstract: A system for the extrapolation of a glucose concentration has a data input device for entering administered insulin doses and their times of administration, a data input device for entering the carbohydrates consumed or to be consumed, a unit for determining an actual glucose concentration at a point in time (ta) in a patient's bodily fluid, a memory unit, and an evaluation unit for evaluation of the data stored in the memory unit, and for the extrapolation of a glucose concentration at a point in time tp, whereby tp is after ta The extrapolation includes determining the portion (Iwirk) of insulin doses that become effective between ta and tp; determining the portion of consumed carbohydrate units KHwirk, that become effective between ta and tp; and determining an extrapolated glucose concentration Gp at the point in time tp with consideration for Iwirk and KHwirk.

Abstract: Novel compounds that are potent inhibitors of HIV reverse transcriptase (RT) are described in the invention. Thes novel compounds also inhibit replication of a retrovirus, such as human immunodeficiency virus-1 (HIV-1). The novel compounds of the invention include analogs and derivatives of phenethylthiazolylthiourea (PETT), of dihydroalkoxybenzyloxopyrimidine (DABO), and of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT). The invention additionally provides a composite HIV reverse-transcriptase (RT) nonnucleoside inhibitor (NNI) binding pocket constructed from a composite of multiple NNI-RT complexes. The composite RT-NNI binding pocket provides a unique and useful tool for designing and identifying novel, potent inhibitors of reverse transcriptase.

Abstract: A method of multivariate spectral analysis, termed augmented classical least squares (ACLS), provides an improved CLS calibration model when unmodeled sources of spectral variation are contained in a calibration sample set. The ACLS methods use information derived from component or spectral residuals during the CLS calibration to provide an improved calibration-augmented CLS model. The ACLS methods are based on CLS so that they retain the qualitative benefits of CLS, yet they have the flexibility of PLS and other hybrid techniques in that they can define a prediction model even with unmodeled sources of spectral variation that are not explicitly included in the calibration model. The unmodeled sources of spectral variation may be unknown constituents, constituents with unknown concentrations, nonlinear responses, non-uniform and correlated errors, or other sources of spectral variation that are present in the calibration sample spectra.

Abstract: The measurement throughput and the precision in sample identification are improved in a tandem type mass spectrograph. Thus, in a mass spectrum analyzing system utilizing a tandem type mass spectrograph in which the selection of an ionic species to serve as the measurement target, dissociation thereof and spectral measurement are repeated in n stages, the ionic species to be measured in MSn is selected based on the mass-to-charge ratios (m/z values) obtained as a result of the spectral analysis in MSn?1 (n?2), and this procedure is repeated until the sequence of a required number of amino acids is determined.

Abstract: A system for analyzing mass spectrometric data is provided, which has an data input means for entering mass spectrometric data of a parent ion and dissociated ions resulting from multiple dissociation of the parent ion, and an analytical means for providing characteristics of a candidate for estimated structure of a precursor ion that is representative of pre-dissociation structure at each stage of dissociation. The system analyzes one of the structure of precursor ion at each stage of dissociation and the structure of parent ion based on the characteristics and spectrometric data.

Abstract: A method for determining an unknown starting quantity of a target nucleic acid sequence in a test sample comprises amplifying the unknown starting quantity of the target nucleic acid sequence in the test sample and known starting quantities of a calibration nucleic acid sequence in respective calibration samples; and determining a respective threshold value for each of the nucleic acid sequences using a derivative of a growth curve derived for the sequence. The starting quantity of the target nucleic acid sequence in the test sample is determined using the threshold value determined for the target sequence and a calibration curve derived from the threshold values determined for the known starting quantities of the calibration nucleic acid sequences.

Abstract: A main object is to cope with an unknown structure substance thereby to identify the structure of a parent ion highly precisely and to derive a supposed structure. A method for analyzing mass spectrometric data is disclosed, which: acquires mass spectrometric data on an ionized sample and dissociated ions dissociated from the sample as a parent ion; derives dissociated ion candidates by analyzing the molecular orbits on the candidates of the structures of the parent ion; and displays the analytical results of the parent ion candidates and the dissociated ion candidates and compares the data of the dissociated ion candidates and the data of dissociated ions actually measured, to evaluate the structures of the parent ion candidates.

Abstract: Methods are disclosed for establishing a quantitative relationship between spectral properties of molecules and a biological, chemical, or physical endpoint of the molecules. Spectral data including data from nuclear magnetic resonance, mass spectrometric, infrared, and ultraviolet-visible techniques are used along with endpoint data to train a pattern-recognition program. The training yields a spectral data-activity relationship that may be used to predict the endpoint value of a molecule from its spectral data alone. Methods for rapidly screening isolated compounds or mixtures of compounds based upon their spectral data are included.

Abstract: An analytical method and apparatus using principal component analysis of nuclear magnetic resonance (NMR) data for rapid molecular structure/function pattern recognition. The presence of a molecular substructure in an organic compound is determined by comparing principal components calculated from chemical shift values of the substructure in selected compounds with those calculated from the chemical shift values of the organic compound. Alternatively, principal components are calculated from the intensities of NMR signals for a full spectrum, or selected regions thereof, to determine whether an organic compound belongs to or is excluded from a set of structurally related compounds. Also, the presence of a pharmacophore in an organic compound can be determined by comparing the principal components derived from data on a set of compounds known to bind to a particular receptor, or have a common biological effect, with the principal components of the data set of the organic compound.

Abstract: The present invention includes three-dimensional models of antibodies, such as Fc-C?/C?4 regions of IgE antibodies, as well as methods to produce such models. The present invention also includes muteins having increased stability and/or antibody receptor binding activity, as well as methods to produce such muteins, preferably using information derived from three-dimensional models of the present invention. Also included are nucleic acid sequences encoding muteins of the present invention and use of those sequences to produce such muteins. Also included is the use of the model to identify compounds that inhibit the binding of an antibody receptor protein to an antibody. The present invention also includes uses of such muteins and inhibitory compounds, for example, in methods to diagnose and protect animals from allergy and other abnormal immune responses.

Abstract: This invention provides a method for rapidly obtaining accurate three-dimensional structure of proteins including large or multi-sub unit proteins, using a combination of NMR analysis of backbone only 13C, 15N or 13C and 15N isotopically labeled proteins which are optionally also 2H isotopically labeled in the C? position protons and residual dipolar coupling measurements in more than one partially aligned state and/or orientation data pertaining to overlapping successive peptide pairs.

Abstract: There is a pressing need for computer-implemented tools that can summarize and present the enormous amounts of public literature to facilitate analysis of gene expression data. The present invention provides techniques and systems for efficiently integrating public literature regarding gene function with data from gene expression profiling experiments. Information from literature databases relating to a particular set of DNA sequences of known expression pattern is retrieved, processed, cross-referenced and viewed to provide further information about a particular DNA sequence to facilitate its identification as a candidate gene.

Abstract: The inventors have modified the amino acid sequence of a maltogenic alpha-amylase to obtain variants with improved properties, based on the three-dimensional structure of the maltogenic alpha-amylase Novamyl. The variants have altered physicochemical properties., e.g. an altered pH optimum, improved thermostability, increased specific activity, an altered cleavage pattern or an increased ability to reduce retrogradation of starch or staling of bread.

Abstract: An automatic peak selection method for multidimensional data that selects peaks from very noisy data such as two-dimensional liquid chromatography-mass spectrometry (LC-MS) data is described. Such data are characterized by non-normally distributed noise that varies in different dimensions. The method computes local noise thresholds for each one-dimensional component of the data. Each point has a local noise threshold applied to it for each dimension of the data set, and a point is selected as a candidate peak only if its value exceeds all of the applied local noise thresholds. Contiguous candidate peaks are clustered into actual peaks. The method is preferably implemented as part of a high-throughput platform for analyzing complex biological mixtures.

Abstract: For use in an integral equation formulation of capacitance, a system for, and method of, generating a representation of charge distribution for a given capacitive structure (which may be an integrated circuit). In one embodiment, the system includes: (1) a charge variation function generator that creates a multidimensional charge variation function that is not directly dependent on a conductive geometry of the structure and (2) a conductive geometry generator, associated with the charge variation generator, that creates a conductive geometry that is independent of charge variation in the structure, the charge variation function and the conductive geometry employable in the integral equation formulation to reduce a complexity thereof.

Abstract: Methods of synthesizing a peptide or peptide-like molecule to a polypeptide or protein target based on mode-matching each member of a set of peptide constituents of the peptide or peptide-like molecule to peptide constituents of the target polypeptide or protein target. Methods are also provided for synthesizing retro-inverso peptides to the mode-matched peptide.

Abstract: A cell-based binning method (“Data Driven” binning method) allows the inclusion of all molecules, generates a high percentage of occupied cells, and provides adequate division of the molecules in the low-dimensional subspaces (typically all one-dimension (1-D), two-dimension (2-D), and three-dimension (3-D) subspaces). A chemical space coverage criterion (“Uniform Cell Coverage (UCC)” criterion) measures the uniformity of coverage of the molecules selected. A fast exchange design algorithm (“fast exchange UCC” algorithm) that minimizes the number of searches of the candidate points while maximizing the number of exchanges during each pass through the candidate points. This method is many times faster than previous exchange algorithms and generates designs with good coverage properties.

Abstract: A computer product for determining thermodynamic properties of a natural gas hydrocarbon, when the speed of sound in the gas is known at an arbitrary temperature and pressure. Thus, the known parameters are the sound speed, temperature, pressure, and concentrations of any dilute components of the gas. The method uses a set of reference gases and their calculated density and speed of sound values to estimate the density of the subject gas. Additional calculations can be made to estimate the molecular weight of the subject gas, which can then be used as the basis for mass flow calculations, to determine the speed of sound at standard pressure and temperature, and to determine various thermophysical characteristics of the gas.

Abstract: The present invention is broadly directed to methods of screening ribosomal protein L11/GTPase activating region (GAR) RNA-modulating compounds by using information from the high-resolution structure of the L11/GAR complex. The methods are useful in identifying compounds useful for anti-bacterial treatments.

Abstract: Applicant has developed a method for predicting the structure of a zeolite including the cation positions and distributions. The method comprises using combinatorial minimization and molecular mechanics techniques. One important aspect of the technique is the bumping of two cations. Another aspect of the invention is predicting the adsorption isotherms of the invention using a biased-Grand Cononical Monte Carlo technique which contains electrostatic and dispersion interaction terms between gas molecules and the zeolite.

Abstract: A method of multivariate spectral analysis, termed augmented classical least squares (ACLS), provides an improved CLS calibration model when unmodeled sources of spectral variation are contained in a calibration sample set. The ACLS methods use information derived from component or spectral residuals during the CLS calibration to provide an improved calibration-augmented CLS model. The ACLS methods are based on CLS so that they retain the qualitative benefits of CLS, yet they have the flexibility of PLS and other hybrid techniques in that they can define a prediction model even with unmodeled sources of spectral variation that are not explicitly included in the calibration model. The unmodeled sources of spectral variation may be unknown constituents, constituents with unknown concentrations, nonlinear responses, non-uniform and correlated errors, or other sources of spectral variation that are present in the calibration sample spectra.

Abstract: A tumor necrosis factor-? converting enzyme (TACE) is produced, purified, and crystallized. The three-dimensional coordinates of the crystal are obtained by X-ray diffraction. The coordinates can be recorded on a computer readable medium, or are part of a video memory, where they can be used as part of a system for studying for studying TACE. The coordinates are also used in designing, screening, and developing compounds that associate with TACE.

Abstract: The present invention relates to pullulanase variants, wherein the variants have improved properties, for example, altered pH optimum, improved thermostability, altered substrate specificity, increased specific activity or altered cleavage pattern. The present invention also relates to methods of making pullulanase variants having at least one altered property based on the three-dimensional structure of a parent pullulanase.

Abstract: A method and apparatus for determining biological sequence sites of interest using client 1 server 3 computer architecture. In the method, one or more users (not shown) use computer client or client 1 to select a biological sequence database 5 of interest, and determines the search parameters 7 which control the specificity of results to be returned. The remote computer client 1 submits the search request 11 to a central computer server 3, which processes search request 11. Once server 3 has received request 14, the claimed method is undertaken by PatternProbe Express 16 and results are returned 18 to one or more remote client(s) 1. Once received, results are viewed 22 according to the previously selected search parameters 7.

Abstract: Minute amounts of material, such as a contaminant, are detected, classified and located using a single procedure that eliminates the need for using complex and sometimes redundant instrumentation setups, multiple (and sometimes overlapping) analytic processes, or both. In one embodiment, a series of processing steps enables one to detect, classify, and localize minute amounts of particular elements, e.g., contaminants, in material being tested. Data sets, suitable for characterizing components of samples at least spectrally and spatially, are collected from at least one uncontaminated sample of material (the “baseline” or “control”) and a sample of material under test (MUT) that may contain contaminants. Comparison of these data sets, using the procedures of the present invention, enables ready classification of minute amounts of material in any sample.

Abstract: The present invention provides a novel four stage ab initio approach for predicting the tertiary structure of polypeptides. The methods of the invention combine the classical and modern views of protein folding, while using free energy calculations and integer linear optimization to predict helical and &bgr;-sheet structures. Derivation of restraints, detailed atomistic modeling, and a deterministic global optimization method, &agr;BB, coupled with torsion angle dynamics, form the basis for the final tertiary structure prediction. The performance of the methods of the invention is illustrated using several different polypeptides.

Abstract: The invention provides the crystal structure of the cytochrome P450 3A4 protein molecule. The structure is set out in Table 5. The structure may be used in to model the interaction of compounds such as pharmaceuticals with this protein, and to determine the structure of related cytochrome P450 molecules.

Abstract: A modular laptop computer for accommodating selective placement and customization of user interface components. The computer includes a cavity having a connection or interface or coupling region, such as a universal serial bus jack for connecting to or mating with a corresponding interface on each component. The interface connections in the cavity are connected to one or more buses for providing an interface between the attached components and a computer processor. In this manner, the components such as keyboards, trackballs, drives, music players and so forth, can all be rearranged within the cavity in the positions of the user's preference.

Abstract: The present invention relates to a data storage medium encoded with the structural coordinates of crystallized molecules and molecular complexes which comprise the active site binding pockets of bacterial IMPDH. Such data storage material is capable of displaying such molecules and molecular complexes, or their structural homologues, as a graphical three-dimensional representation on a computer screen. This invention also relates to methods of using the structure coordinates to solve the structure of homologous proteins or protein complexes. In addition, this invention relates to methods of using the structure coordinates to screen and design compounds, including inhibitory compounds, that bind to IMPDH or homologues thereof. This invention also relates to molecules and molecular complexes that comprise the active site binding pockets of IMPDH or close structural homologues of the active site binding pockets.

Abstract: The present invention provides a computer-assisted method for creating and displaying a model of a molecule in which residues that are affected by the binding of a ligand to the molecule are highlighted, making it possible to trace the path of propagation of a binding signal through the molecule. In order to carry out the method, the binding site determinants of the molecule are determined and the binding constant for the ligand is calculated. The states of a conformational ensemble that are binding competent are identified, and the Gibbs energy and probability of each state and the stability constant per residue of the molecule are calculated in the presence and absence of the ligand. Those residues that display a difference in stability constant in the presence vs absence of ligand are those which are affected by the binding of the ligand.

Abstract: The invention relates to a method and an apparatus for the on-line analysis of liquid substance mixtures by means of NIRS. For evaluation by spectral data comparison, merely the binary mixtures of the possible components in quantitative graduations are used as calibration spectra. In order to accelerate the evaluation, all data points of a spectrum are summated, and each spectrum is characterized by only one characteristic number.

Abstract: A method for generating a numeric or alpha-numeric identifier representative of a chemical structure having at least two atoms connected by a bond includes the step of assigning a numerical value to each atom and a numerical bond value to each bond. The method updates the numerical values for each atom based on the current values assigned to each atom and the numerical bond value. After the numerical values for each atom have been updated, the method calculates a numeric or alpha-numeric identifier for the chemical structure.

Abstract: Techniques for analyzing gene expression levels are provided. In one aspect of the invention, the technique provides a method for determining a concentration level of a target nucleic acid, the target nucleic acid comprising at least one target oligonucleotide. The method determines (i) a measure of affinity value of the target oligonucleotide with a probe oligonucleotide; and (ii) a hybridization intensity value for the target oligonucleotide and the probe oligonucleotide at a probe spot. The measure of affinity value and the hybridization intensity value are used to determine the concentration level of the target nucleic acid.

Abstract: Systems and methods are described for processing an emission signal, such as a fluorescent signal, to compensate for noise in an excitation beam, such as a laser beam. As one example, a scanning system is described that includes an excitation signal generator that provides an excitation signal having one or more representative excitation values representative of an excitation beam; an excitation reference provider that provides at least one excitation reference value; a normalization factor generator that compares the excitation reference value to at least one representative excitation value, thereby generating a normalization factor; and a comparison processor that adjusts at least one emission value corresponding to the at least one representative excitation value based, at least in part, on the normalization factor.

Abstract: A polymer comprising units (1) derived from an alpha-olefin having at least 3 carbon atoms (1′), units (2) derived from divinylbenzene or C1-10hydrocarbyl substituted derivatives thereof (2′), and units (3) derived from ethylene (3′), the polymer comprising at least 75 mole % of units (1), from 0.01 to 5 mole % of units (2), and up to 20 mole % of units (3), the polymer having a branching factor BF 0.75.

Abstract: The use for biological screening purposes of a subset (library) of a large combinatorially accessible chemical universe increases the efficiency of the screening process only if the subset contains members representative of the total diversity of the universe. In order to insure inclusion in the subset of molecules representing the total diversity of the universe under consideration, valid molecular descriptors which quantitatively reflect the diversity of the molecules in the universe are required. A unique validation method is used to examine both a new three dimensional steric metric and some prior art metrics. With this method, the relative usefulness/validity of individual metrics can be ascertained from their application to randomly selected literature data sets.

Abstract: A method for specifying a multi-component composition without human intervention includes customer specification of at least two physical property limitations, and determination of a recommended composition meeting those limitations using a continuous model relating the physical properties to the compositional variables. The method may extend to supplying a multi-component composition by further including one or more of calculating the cost of the recommended composition, calculating the price of the recommended composition, formulating a contracted amount of the recommended composition, and billing for a contracted amount of the recommended composition.