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PubMed1999

A comfortable brain-interface to video displays.

Recent progress in and the popularization of computer graphics mean we now see many images that are composed artificially and include a lot of flicker to add to their impact. These highly flickering images, however, cause fatigue that affects our brain rather than our eyes. This is a content-dependent video display terminal (VDT) hazard that is unlike conventional VDT hazards. This paper shows that content-dependent VDT hazards are a genuine threat based on physiological evidence concerning the temporal response of visual cortical cells, and proposes a quantitative measure to estimate the risk of the hazard, and also provides an adaptive filtering method to reduce the risk. Images from the critical part of the "Pocket Monsters" TV animation episode were studied to confirm the effectiveness of this method.

Journal Article↗
PubMed1995

Advances in interactive craniofacial surgery planning by 3D simulation and visualization.

In craniofacial surgery careful preoperative planning is essential. Traditional preoperative work-up consists of cast model surgery, cephalometric prediction tracing and analysis of photographs. Recently, we introduced 3-dimensional (3D) computed tomography (CT) model surgery in our preoperative work-up and presurgical prediction of the postoperative result. However, only limited information can be extracted concerning soft tissue changes which are most important for the patients' postoperative appearance. We propose a new system which will allow a precise preoperative visualization of not only bony structures but also the soft tissue surfaces. 3D CT data of the skull are integrated with 3D surface data acquired by laser scanning. Based on the 3D CT data the bony structures are segmented automatically and processed interactively to simulate the planned surgical procedure. Afterwards, the 3D soft tissue changes resulting from the shifting of bony segments are computed. The postoperative appearance of the patient is visualized using computer animation techniques.

Algorithms↗
PubMed2001

Computational methods for RNA structure determination.

During the past year, major improvements have been made in methods used to solve RNA structures from crystals, find RNA patterns in sequence data and determine RNA secondary structure. Computational methods for assisting an interactive computer graphics human modeler, searching the conformational space of RNA tertiary structure, studying the dynamics of complexes involving RNA and simulating RNA catalytic activities have also been advanced.

Base Sequence↗
PubMed1999

Design and synthesis of 6-(6-D-ribitylamino-2,4-dihydroxypyrimidin-5-yl)-1-hexyl phosphonic acid, a potent inhibitor of lumazine synthase.

A novel inhibitor of lumazine synthase, the penultimate enzyme in the biosynthesis of riboflavin, has been synthesized. The inhibitor was designed by computer graphics molecular modeling using a hypothetical structure of the enzyme-inhibitor complex. The new compound is relatively potent when compared with the known inhibitors, and displays a KI of 109 microM.

Bacillus subtilis↗
PubMed1994

A three-dimensional model of hepatitis delta virus ribozyme based on biochemical and mutational analyses.

BACKGROUND: Hepatitis delta virus (HDV), which has a single-stranded RNA genome about 1700 nucleotides long, is a satellite virus of hepatitis B, and is associated with a high incidence of fulminant hepatitis and death in infected humans. Like certain pathogenic subviral RNAs that infect plants, HDV RNA features a closed-circular conformation, a rolling-circle mechanism of replication and RNA-catalyzed self-cleaving reactions of both genomic and anti-genomic strands in vitro. The catalytic domains cannot be folded into either the hammerhead or hairpin secondary-structure motifs that have been found in other self-cleaving RNAs. RESULTS: A pseudoknot secondary-structure model has been suggested for the catalytic domain (ribozyme) of HDV RNA. We conducted extensive mutational analyses of regions of the HDV ribozyme predicted in this model to be single stranded, and found that several of them are important for catalytic activity. We used these data, sequence comparisons between different isolates and previously published structural analyses to produce a computer graphic model of the three-dimensional architecture of the HDV ribozyme. CONCLUSIONS: Our model supports the pseudoknotted structure and rationalizes several observations relating to the lengths of the various stems and the sequence requirements of the single-stranded regions. It also provides insight into the catalytic mechanism of the HDV ribozyme. We specifically propose that residues C75, U20 and C21 form the basis of the catalytic region and are close to the cleavable phosphate.

Base Sequence↗
PubMed2002

The Drosophila standard brain.

Organisms and organs come in sizes and shapes. With size, science has no problems, but how to quantify shape? How similar are two birds or two brains? This problem is particularly pressing in cases like brains where structure reflects function. The problem is not new, but satisfying solutions have yet to be worked out. For brain anatomy, no general methodology for a statistically secured quantitative description is available. Using the small brain of the fly Drosophila melanogaster, we have explored a new approach combining immunohistochemistry, high-resolution 3D confocal microscopy, and advanced graphics computing. For a genetic model organism such as Drosophila, a quantitative assessment of brain structure is particularly rewarding, since it allows for the identification of genetic variants with subtle brain structure phenotypes and, even more importantly, the organization of the wealth of gene expression patterns in the brain into a genetic atlas linking molecular and organismic gene function. We now provide a representative standard for the brain of D. melanogaster wild-type with means and variances for several aspects of its shape. Its application to volumetry, mutants, and gene expression patterns is demonstrated.

Animals↗
PubMed2000

Do the hamstrings and adductors contribute to excessive internal rotation of the hip in persons with cerebral palsy?

Children with cerebral palsy frequently walk with excessive internal rotation of the hip. Spastic medial hamstrings or adductors are presumed to contribute to the excessive internal rotation in some patients; however, the capacity of these muscles to produce internal rotation during walking in individuals with cerebral palsy has not been adequately investigated. The purpose of this study was to determine the hip rotation moment arms of the medial hamstrings and adductors in persons who walk with a crouched, internally-rotated gait. Highly accurate computer models of three subjects with cerebral palsy were created from magnetic resonance images. These subject-specific models were used in conjunction with joint kinematics obtained from gait analysis to calculate the rotational moment arms of the muscles at body positions corresponding to each subject's internally-rotated gait. Analysis of the models revealed that the medial hamstrings, adductor brevis, and gracilis had negligible or external rotation moment arms throughout the gait cycle in all three subjects. The adductor longus had an internal rotation moment arm in two of the subjects, but the moment arm was small (<4 mm) in each case. These findings indicate that neither the medial hamstrings nor the adductor brevis, adductor longus, or gracilis are likely to be important contributors to excessive internal rotation of the hip. This suggests that these muscles should not be lengthened to treat excessive internal rotation of the hip and that other factors are more likely to cause internally-rotated gait in these patients.

Adolescent↗
PubMed1998

Potent and specific inhibition of human leukocyte elastase, cathepsin G and proteinase 3 by sulfone derivatives employing the 1,2,5-thiadiazolidin-3-one 1,1 dioxide scaffold.

This paper describes the results of structure-activity relationship studies in a series of heterocyclic mechanism-based inhibitors based on the 1,2,5-thiadiazolidin-3-one 1,1 dioxide scaffold I and capable of interacting with the Sn and Sn' subsites of a serine proteinase. Sulfone derivatives of I were found to be highly effective, time-dependent inhibitors of human leukocyte elastase (HLE), cathepsin G (Cat G) and proteinase 3 (PR 3). The judicious selection of an R1 group (accommodated at the primary specificity site S1) that is based on the known substrate specificity of a target serine proteinase, was found to yield highly selective inhibitors. The presence of a benzyl group (R2 = benzyl) at the S2 subsite was found to lead to a pronounced enhancement in inhibitory potency. Furthermore, the effective use of computer graphics and modeling has led to the design of potent, water-soluble inhibitors. The results of these studies demonstrate that the 1,2,5-thiadiazolidin-3-one 1,1, dioxide platform provides an effective means for appending recognition elements in a well-defined vector relationship, and in fashioning highly-selective and potent inhibitors of serine proteinases.

Cathepsin G↗
PubMed2000

A method for including protein flexibility in protein-ligand docking: improving tools for database mining and virtual screening.

Second-generation methods for docking ligands into their biological receptors, such as FLOG, provide for flexibility of the ligand but not of the receptor. Molecular dynamics based methods, such as free energy perturbation, account for flexibility, solvent effects, etc., but are very time consuming. We combined the use of statistical analysis of conformational samples from short-run protein molecular dynamics with grid-based docking protocols and demonstrated improved performance in two test cases. Our statistical analysis explores the importance of the average strength of a potential interaction with the biological target and optionally applies a weighting depending on the variability in the strength of the interaction seen during dynamics simulation. Using these methods, we improved the num-top-ranked 10% of a database of drug-like molecules, in searches based on the three-dimensional structure of the protein. These methods are able to match the ability of manual docking to assess likely inactivity on steric grounds and indeed to rank order ligands from a homologous series of cyclooxygenase-2 inhibitors with good correlation to their true activity. Furthermore, these methods reduce the need for human intervention in setting up molecular docking experiments.

Combinatorial Chemistry Techniques↗
PubMed2000

An automatic homology modeling method consisting of database searches and simulated annealing.

We introduce a method of homology modeling consisting of database searches and simulated annealing. All processes involving searches for homologous proteins, alignment, the construction of Calpha atoms, construction of main-chain atoms, and the construction of side-chain atoms are performed automatically. In this method, main-chain conformations are generated from the weighted average of mainchain coordinates in reference proteins. The weight is defined by the local space homology representing the similarity of environmental residues at topologically equivalent positions in reference proteins. Side-chain conformations are generated for constructed main-chain atoms by database searches, and main-chain atoms are optimized for the fixed side-chain conformations. These two processes, i.e., the side-chain generation and main-chain optimization, are repeated several times. This type of construction provides a structure similar to the x-ray structure, in particular, for main-chain and side-chain atoms in the residues belonging to structurally conserved regions (SCRs). The accuracy of our method was evaluated for 14 proteins whose structures are known. The average root mean square deviation between models and x-ray structures was 2.29 A for all atoms, and the percentage of chi1 angles within 30 degrees was 72.6% for SCRs residues. Some models were in good agreement with their respective x-ray structures. Our method, which has the advantage of being automated, gives results similar to, or better than, published results for three widely used test proteins. Our software, FAMS, is available on the World Wide Web.

Amino Acid Sequence↗
PubMed2000

Docking of sulfonamides to carbonic anhydrase II and IV.

Starting with a known active site of a protein and a database of compounds, one would like to quickly identify a few compounds that "dock" into the active site and obtain "good" binding free energies. The main goal of current automated docking procedures is to predict the "best" substrate-enzyme complex while other programs such as UHBD and DelPhi can be used to compute binding free energies. In this paper, we will focus on the application of docking methods and parameters to study substrate-enzyme interactions of a metalloenzyme system. Specifically, we report on the docking of sulfonamides to carbonic anhydrase II and IV, which are of interest due to their application in glaucoma therapy. Using a standard docking protocol, it is possible to correctly predict not only the orientation of inhibitors to a specific isozyme, but also determine the qualitative affinity for a group of inhibitor for an isozyme.

Algorithms↗
PubMed2000

SymROP: ROP protein with identical helices redesigned by all-atom contact analysis and molecular dynamics.

Experience has shown that protein redesigns (using the backbone from a known protein structure) are far more likely to produce well-ordered, native-like structures than are true de novo designs. Therefore, to design a four-helix bundle made of identical short helices, we here proceed by an extensive redesign of the ROP protein. A fully symmetrical SymROP sequence derived from ROP was chosen by modeling ideal-geometry side chains, including hydrogens, while maintaining the "goodness-of-fit" of side-chain packing by calculating all-atom contact surfaces with the Reduce and Probe programs. To estimate the probable extent of backbone movement and side-chain mobility, restrained molecular dynamics simulations were compared for candidate sequences and controls, including substitution of Abu for all or half the core Ala residues. The resulting 17-residue designed sequence is 41% identical to the relevant regions in ROP. SymROP is intended for construction by the Template Assembled Synthetic Proteins approach, to control the bundle topology, to use short helices, and to allow blocked termini and unnatural amino acids. ROP protein has been a valuable system for studying helical protein structure because of its simplicity and regularity within a structure large enough to have a real hydrophobic core. The SymROP design carries that simplicity and regularity even further.

Amino Acid Sequence↗
PubMedDate not supplied

Designing targeted libraries with genetic algorithms.

In combinatorial synthesis, molecules are assembled by linking chemically similar fragments. Because the number of available chemical fragments often greatly exceeds the number that can be used in one synthetic experiment, one needs a rational method for choosing a subset of desirable fragments. If a combinatorial library is to be targeted against a particular biological activity, virtual screening methods can be used to predict which molecules in a virtual library are most likely to be active. When the number of possible molecules in a virtual library is very large, genetic algorithms (GAs) or simulated annealing can be used to quickly find high-scoring molecules by sampling a small subset of the total combinatorial space. We previously demonstrated how a GA can be used to select a subset of fragments for a combinatorial library, and we used topology-based methods of scoring. Here we extend that earlier work in three ways. (1) We demonstrate use of the GA with 3D scoring methods developed in our laboratory. (2) We show that the approach of assembling libraries from fragments in high-scoring molecules is a reasonable one. (3) We compare results from a library-based GA to those from a molecule-based GA.

Algorithms↗
PubMedDate not supplied

Synergy between combinatorial chemistry and de novo design.

Traditional de novo design algorithms are able to generate many thousands of ligand structures that meet the constraints of a protein structure, but these structures are often not synthetically tractable. In this article, we describe how concepts from structure-based de novo design can be used to explore the search space in library design. A key feature of the approach is the requirement that specific templates are included within the designed structures. Each template corresponds to the "central core" of a combinatorial library. The template is positioned within an acyclic chain whose length and bond orders are systematically varied, and the conformational space of each structure that results (core plus chain) is explored to determine whether it is able to link together two or more strongly interacting functional groups or pharmacophores located within a protein binding site. This fragment connection algorithm provides "generic" 3D molecules in the sense that the linking part (minus the template) is built from an all-carbon chain whose synthesis may not be easily achieved. Thus, in the second phase, 2D queries are derived from the molecular skeletons and used to identify possible reagents from a database. Each potential reagent is checked to ensure that it is compatible with the conformation of its parent 3D conformation and the constraints of the binding site. Combinations of these reagents according to the combinatorial library reaction scheme give product molecules that contain the desired core template and the key functional/pharmacophoric groups, and would be able to adopt a conformation compatible with the original molecular skeleton without any unfavorable intermolecular or intramolecular interactions. We discuss how this strategy compares with and relates to alternative approaches to both structure-based library design and de novo design.

Algorithms↗
PubMedDate not supplied

Development and screening of a polyketide virtual library for drug leads against a motilide pharmacophore.

A virtual library of macrocyclic polyketide molecules was generated and screened to identify novel, conformationally constrained potential motilin receptor agonists ("motilides"). A motilide pharmacophore model was generated from the potent 6,9-enol ether erythromycin and known derivatives from the literature. The pharmacophore for each molecular conformation was a point in a distance-volume space based on presentation of the putative binding moieties. Two methods, one fragment based method and the other reaction based, were explored for constructing the polyketide virtual library. First, a virtual library was assembled from monomeric fragments using the CHORTLES language. Second, the virtual library was assembled by the in silico application of all possible polyketide synthase enzyme reactions to generate the product library. Each library was converted to low-energy 3D conformations by distance geometry and standard minimization methods. The distance-volume metric was calculated for low-energy conformations of the members of the virtual polyketide library and screened against the enol ether pharmacophore. The goal was to identify novel macrocycles that satisfy the pharmacophore. We identified three conformationally constrained, novel polyketide series that have low-energy conformations satisfying the distance-volume constraints of the motilide pharmacophore.

Combinatorial Chemistry Techniques↗
PubMedDate not supplied

Novel algorithms for the optimization of molecular diversity of combinatorial libraries.

Various approaches to measuring and optimizing molecular diversity of combinatorial libraries are presented. The need for different diversity metrics for libraries consisting of discrete molecules ("cherry picking") vs libraries formed from combinatorial R-group enumeration (array-based selection) is discussed. Ideal requirements for diversity metrics applied to array-based selection are proposed, focusing, in particular, on the concept of incremental diversity, i.e., the change in diversity as redundant or nonredundant molecules are added to a compound collection or combinatorial library. Several distance and cell-based diversity functions are presented and analyzed in terms of their ability to satisfy these requirements. These diversity functions are applied to designing diverse libraries for two test cases, and the performance of the diversity functions is assessed. Issues associated with redundant molecules in the virtual library are discussed and analyzed using one of the test examples. The results are compared to reagent-based diversity optimizations, and it is shown that a product-based diversity protocol can result in significant improvements over a reagent-based scheme based on the diversity obtained for the resulting libraries.

Algorithms↗
PubMedDate not supplied

Combinatorial library design for diversity, cost efficiency, and drug-like character.

Most computational techniques for the design of combinatorial libraries have concentrated solely on maximizing the diversity of the selected subset or its similarity to a known target. However, such libraries can produce high-throughput screening hits with properties that make them unsuitable to take forward into medicinal chemistry. This article describes software that allows the design of library subsets to simultaneously optimize a library's diversity or similarity to a target, properties (such as drug likeness) of the library members, properties (such as cost) of the reagents required to make them, and efficiency of synthesis in arrays or mixtures. Example are given showing that libraries can be designed to contain drug-like molecules with only a small trade-off in terms of the maximum possible diversity, and that the cost of the library, in terms of the reagents required to make it, can be contained. Other examples show that libraries can be designed to minimize the deconvolution problem or to maximize the number of molecules predicted to be active while also being designed for efficiency of synthesis.

Algorithms↗