Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “computational design”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 469 records · Page 26Linked to original sources
PubMedDate not supplied

Computer simulations of patellofemoral joint surgery. Patient-specific models for tuberosity transfer.

BACKGROUND: Variable clinical outcomes of tibial tuberosity transfer surgery have been reported. HYPOTHESES: The biomechanical outcome of surgery is patient-specific; no single procedure produces superior results for all patients. Use of patient-specific computer models can optimize choice of procedure. STUDY DESIGN: Computer simulation study using clinical data. METHODS: We used patient-specific multibody models of the patellofemoral joints of 20 patients with a diagnosis of patellar subluxation and osteoarthritis. Four tibial tuberosity transfer procedures (two anterior and two anteromedial) were simulated for each patient and compared with their preoperative model. RESULTS: When results for all patients were averaged, all simulated operations produced a statistically significant decrease in surface-wide mean contact stress, although no significant difference was found among them. CONCLUSIONS: The simulated surgical outcomes were patient-specific: no single procedure was consistently superior at decreasing peak or mean stress and each procedure produced a potentially detrimental outcome, an increase in either mean stress or peak stress, in at least one patient. CLINICAL RELEVANCE: Computer simulation may serve as a valuable tool for tailoring procedures to specific patients.

Biomechanical Phenomena↗
PubMed1990

The development of new radiopharmaceuticals.

The development of new radiopharmaceuticals is the basis of the continuing growth of nuclear medicine. Chemical interactions of electron clouds in their three-dimensional conformations bring together, in the process of molecular recognition, the reaction of antibody and antigen, receptor and ligand, enzyme and substrate, hormone and response site. This convergence enables the computer design of molecules such as ligands to fit computer-displayed conformational models showing active centres, positive and negative charges and other interactions. Indeed, given a particular molecule, a complementary binding structure can be devised. The hybridoma approach to monoclonal antibody production is being superceded by the bacterial bioengineer. The gene for the hypervariable region from the spleen cells of immunized mouse can be coupled with the myeloma gene. The polymerase chain reaction can duplicate the DNA a million times over in 20 min and the result transfected into a bacterial plasmid to produce the antibody. These scientific problems are soluble in principle and are being solved. However, so much damage to this developing biological field is being done by regulatory authorities that one must ask who should or can regulate the regulators. These problems have to be overcome in order to provide the new radiopharmaceuticals that are the food and wine of nuclear medicine.

Animals↗
PubMed2002

Pulse cleaning flow models and numerical computation of candle ceramic filters.

Analytical and numerical computed models are developed for reverse pulse cleaning system of candle ceramic filters. A standard turbulent model is demonstrated suitably to the designing computation of reverse pulse cleaning system from the experimental and one-dimensional computational result. The computed results can be used to guide the designing of reverse pulse cleaning system, which is optimum Venturi geometry. From the computed results, the general conclusions and the designing methods are obtained.

Air Movements↗
PubMed1992

The hardware components of a computer system.

The two goals of this article are to give you a very brief overview of the evolution of computing and an introduction to the elements of a computer. The birth of the modern computer can be traced to John von Neumann. The model he proposed consisted of four major parts: the control unit, the arithmetic unit, the memory, and the input/output unit. His concept for a "stored program" computer provided the foundation for five decades of computer designs.

Computer Systems↗
PubMed1996

The cell sectioning model. Nuclear/cytoplasmic ratio studied by computer simulation.

OBJECTIVE: Stereologic analysis can be supported using methods of modeling and simulation. To illustrate the use of a mathematical cell sectioning model (CSM) in predicting two-dimensional (2-D) measurement characteristics of sectioned cells by means of computer-assisted simulation, the present study was performed. STUDY DESIGN: Computer software based on the CSM was developed to simulate 2-D nuclear/cytoplasmic (N/C) ratio distributions and to test the sensitivity of the parameter to several factors. Simulations were performed with the following feature set for cells of simulated populations: (1) size, shape (approximated by an ellipsoid of rotation) and orientation of the cell, and (2) size, shape and intracellular position of the nucleus. RESULTS: The computer tests showed that the value of the 2-D N/C ratio depends upon many factors; the real three-dimensional N/C ratio is only one. Statistical characteristics of a 2-D N/C ratio sample were found to be sensitive to changes in (1) the nuclear position inside the cell, (2) cell shape, and (3) orientation of the asymmetric cell with respect to a cutting plane. CONCLUSION: CSM tests demonstrated the model validity of and potentials for using it as an algorithm for morphometry software. Taking into account the sensitivity of the 2-D N/C ratio parameter to various factors, great care must be used in interpreting its observations.

Animals↗
PubMed1995

Computed tomographic evaluation of the normal adult odontoid. Implications for internal fixation.

STUDY DESIGN: Computed tomography scans of the dens were performed on patients who had no atlantoaxial pathology. OBJECTIVES: To determine whether one or two screws is optimal for fracture fixation and whether two screws can always negotiate the intramedullary odontoid cavity. SUMMARY OF BACKGROUND DATA: Fixation of Type II dens fractures traditionally has used C1-C2 posterior wiring and fusion. Two screws placed across an odontoid fracture as a method of rigid internal fixation also has been described. However, it is not known whether two screws can always negotiate the odontoid canal. METHODS: Ninety-two consecutive computerized tomography scans of the dens were performed on adults who had no atlantoaxial pathology. Measurements were taken from the scan and compared with the cross-sectional diameter of two odontoid screws. RESULTS: The critical diameter for the placement of two 3.5-mm cortical screws with tapping was 9.0 mm. This dimension was present in 95% of the patients studied. CONCLUSIONS: Correct orientation of the computerized tomography scanner is critical for accurate measurements. Two 3.5-mm screws can be used in internal fixation of Type II dens fractures in 95% of the patients if the inner cortex is tapped.

Adolescent↗
PubMed2004

Bivalent tethering of SspB to ClpXP is required for efficient substrate delivery: a protein-design study.

SspB homodimers deliver ssrA-tagged substrates to ClpXP for degradation. SspB consists of a substrate binding domain and an unstructured tail with a ClpX binding module (XB). Using computational design, we engineered an SspB heterodimer whose subunits did not form homodimers. Experiments with the designed molecule and variants lacking one or two tails demonstrate that both XB modules are required for strong binding and efficient substrate delivery to ClpXP. Assembly of stable SspB-substrate-ClpX delivery complexes requires the coupling of weak tethering interactions between ClpX and the SspB XB modules as well as interactions between ClpX and the substrate degradation tag. The ClpX hexamer contains three XB binding sites, one per N domain dimer, and thus binds strongly to just one SspB dimer at a time. Because different adaptor proteins use the same tethering sites in ClpX, those which employ bivalent tethering, like SspB, will compete more effectively for substrate delivery to ClpXP.

Adenosine Triphosphatases↗
PubMedDate not supplied

Fundamentals of computerised data acquisition in the human performance laboratory.

Researchers of the future will depend upon computer technology to address questions that previously could not be answered using traditional methods of data acquisition. Recent advances in computer design and software availability have eliminated many of the limitations previously associated with computer use in the laboratory setting. Although computerisation facilitates the acquisition of laboratory data, identification of errors introduced into the measurement is often more difficult. The laboratory computer is only one component of an automated data acquisition system. A system designed to collect physiological data comprises several primary components, including: (a) sensing element; (b) signal amplification/conditioning circuits; (c) analogue display; (d) computer interface; (e) laboratory computer; and (f) acquisition software. The acquisition and conditioning of analogue signals is accomplished using traditional laboratory procedures familiar to the researcher. Converting this analogue signal into a digital format used by the computer, however, represents new techniques. Fundamentals of computerised data acquisition are discussed. An understanding of how an automated data acquisition system is configured and the techniques used to transform the values will assist the user in identifying sources of error introduced into the measurement. Additionally, familiarization with the methods of computerisation will provide insight into future applications of computer technology in the human performance laboratory.

Analog-Digital Conversion↗
PubMed2004

LINC: biology's revolutionary little computer.

The 1963 LINC (Laboratory INstrument Computer) stands at the center of two stories: the computerization of the biologist's laboratory and the advent of small-scale computing. The brainchild of Wesley Clark, 'the most brilliant computer designer of his generation', LINC was developed specifically to address the failure of biologists to adopt computer technology. To meet their unique needs, Clark built a machine the radical design of which defied and subverted the then dominant conventions of computer architecture.

Biology↗
PubMed2000

GRID/CPCA: a new computational tool to design selective ligands.

We present a computational procedure aimed at understanding enzyme selectivity and guiding the design of drugs with respect to selectivity. It starts from a set of 3D structures of the target proteins characterized by the program GRID. In the multivariate description proposed, the variables are organized and scaled in a different way than previously published methodologies. Then, consensus principal component analysis (CPCA) is used to analyze the GRID descriptors, allowing the straightforward identification of possible modifications in the ligand to improve its selectivity toward a chosen target. As an important new feature the computational method is able to work with more than two target proteins and with several 3D structures for each protein. Additionally, the use of a 'cutout tool' allows to focus on the important regions around the active site. The method is validated for a total number of nine structures of the three homologous serine proteases thrombin, trypsin, and factor Xa. The regions identified by the method as being important for selectivity are in excellent agreement with available experimental data and inhibitor structure-activity relationships.

Algorithms↗
PubMed1993

Strategies for indirect computer-aided drug design.

This review is intended to describe some of the methods and procedures used for computer-aided drug design when the structure of the macromolecular target is unknown, as is the case for CNS active drugs. Strategies and methods used in computer-aided design of drugs in such instances must be "indirect," i.e., focusing on the characterization of the ligands themselves. This situation is different from one in which the three-dimensional structure of the macromolecular target for a drug is known, for example, for drugs that are enzyme inhibitors, allowing "direct" characterization of ligand-receptor interactions. Two qualitatively different "indirect" approaches are described here. One, called 2D-QSAR, is briefly reviewed. It is based on delineating regression relationships between a specified biological end point and properties of the compounds eliciting it. The other, based on pharmacophore development, constitutes the main part of this review. Several levels of pharmacophore development are described, which differ in the extent to which they encompass fundamental molecular properties that are determinants of receptor recognition and activation. The strengths and limitations of each procedure are discussed and illustrated by examples. Two methods for obtaining model receptor structures are then briefly described. Both rely on the prior success of the indirect methods in obtaining ligand properties that modulate receptor recognition and activation. These emerging capabilities have the potential to bridge the gap between indirect and direct methods of drug design, since, if successful, the design process can continue in a direct mode using explicit characterization of drug-receptor interactions. Strategies for hypothesis validation and use of hypothesis for drug design and discovery are also briefly reviewed. The final sections of this review describe specific computational tools such as molecular mechanics and quantum mechanical methods used to characterize and identify relevant molecular properties and indicate some areas for future development of computational chemistry methods that could increase its effectiveness in the design of novel drugs.

Computer Simulation↗
PubMed2005

Computational de novo design and characterization of a four-helix bundle protein that selectively binds a nonbiological cofactor.

We report the complete de novo design of a four-helix bundle protein that selectively binds the nonbiological DPP-Fe(III) metalloporphyrin cofactor (DPP-Fe(III) = 5, 15-Di[(4-carboxymethyleneoxy)phenyl]porphinato iron(III)). A tetrameric, D2-symmetric backbone scaffold was constructed to encapsulate two DPP-Fe(III) units through bis(His) coordination. The complete sequence was determined with the aid of the statistical computational design algorithm SCADS. The 34-residue peptide was chemically synthesized. UV-vis and CD spectroscopy, size-exclusion chromatography, and analytical ultracentrifugation indicated the peptide undergoes a transition from a predominantly random coil monomer to an alpha-helical tetramer upon binding DPP-Fe(III). EPR spectroscopy studies indicated the axial imidazole ligands were oriented in a perpendicular fashion, as defined by second-shell interactions that were included in the design. The 1-D 1H NMR spectrum of the assembled protein displayed features of a well-packed interior. The assembled protein possessed functional redox properties different from those of structurally similar systems containing the heme cofactor. The designed peptide demonstrated remarkable cofactor selectivity with a significantly weaker binding affinity for the natural heme cofactor. These findings open a path for the selective incorporation of more elaborate cofactors into designed scaffolds for constructing molecularly well-defined nanoscale materials.

Amino Acid Sequence↗
PubMed2006

Design of functional ferritin-like proteins with hydrophobic cavities.

Ferritin four-helix bundle subunits self-assemble to create a stable multimer with a large central hydrophilic cavity where metal ions bind. To explore the versatility of this reaction vessel, computational design was used to generate cavities with increasingly apolar surface areas inside a dodecameric ferritin-like protein, Dps. Cavity mutants, in which as many as 120 surface accessible hydrophilic residues were replaced with hydrophobic amino acids, were shown to still assemble properly using size-exclusion chromatography and dynamic light scattering measurements. Wild-type Dps exhibited highly cooperative subunit folding and assembly, which was monitored by changes in Trp fluorescence and UV circular dichroism. The hydrophobic cavity mutants showed distinctly less cooperative unfolding behavior, with one mutant forming a partially assembled intermediate upon guanidine denaturation. Although the stability of Dps to such denaturation decreased with increasing apolar surface area, all proteins exhibited high melting temperatures, T(m) = 74-90 degrees C. Despite the large number of mutations, near-native ability to mineralize iron was maintained. This work illustrates the versatility of the ferritin scaffold for engineering large protein cavities with novel properties.

Bacterial Proteins↗
PubMed2002

On the solution of mixed-integer nonlinear programming models for computer aided molecular design.

This paper addresses the efficient solution of computer aided molecular design (CAMD) problems, which have been posed as mixed-integer nonlinear programming models. The models of interest are those in which the number of linear constraints far exceeds the number of nonlinear constraints, and with most variables participating in the nonconvex terms. As a result global optimization methods are needed. A branch-and-bound algorithm (BB) is proposed that is specifically tailored to solving such problems. In a conventional BB algorithm, branching is performed on all the search variables that appear in the nonlinear terms. This translates to a large number of node traversals. To overcome this problem, we have proposed a new strategy for branching on a set of linear branchingfunctions, which depend linearly on the search variables. This leads to a significant reduction in the dimensionality of the search space. The construction of linear underestimators for a class of functions is also presented. The CAMD problem that is considered is the design of optimal solvents to be used as cleaning agents in lithographic printing.

Journal Article↗
PubMed1992

A computer-aided socket design procedure for above-knee prostheses.

A computer-aided socket design procedure (CASD) has been developed whereby an above-knee socket shape can be created based on anthropometric measurements taken from an amputee. The anthroometric measurements are used to select a subset of three reference shapes from a Reference Shape Library stored in the computer in the form of three-dimensional numerical data. Transformation procedures then scale the reference shapes at each cross-sectional level to match the amputee's cross-sectional areas. Blending of the three shapes is determined by tissue mass weighting factors, to yield a single custom socket configuration, known as the "basic socket shape." Subsequent graphical procedures in the CASD system allows further sculpting of the shape in the form of interactive adjustments of the numerical data to reach the socket shape desired by the prosthetist. The resultant shape data can then be transferred to a computer numerically controlled (CNC) milling machine to carve a model of the socket shape.

Artificial Limbs↗
PubMed1992

Design and recognition properties of a hydropathically complementary peptide to human interleukin 1 beta.

A computer-designed hydropathically complementary peptide to human interleukin 1 beta (IL1 beta) precursor sequence 204-215 recognized the 204-215 peptide as well the entire IL1 beta protein with binding affinities in the micromolar range. Interaction between the complementary pair was characterized by analytical high-performance liquid affinity chromatography on columns derivatized with the computer-generated peptide. Recognition selectivity was clearly shown by the ability of the computer-generated complementary peptide columns to purify the IL1 beta-(204-215)-peptide from complex synthetic mixtures with high yields, independently of the type of solid support used. Recognition specificity was demonstrated by the inability of the IL1 beta-(204-215)-peptide and IL1 beta molecules to interact with blank columns or columns derivatized with other non-related peptides. Furthermore, scrambling the sequence of the computer-generated peptide or the IL1 beta-(204-215)-peptide in such a way as to alter their hydropathic profiles had the effect of abolishing binding. The complementary pair failed to interact in the presence of competing peptide, thus providing further evidence of specificity. Computer-generated complementary peptide affinity columns also proved useful for purification of recombinant human IL1 beta protein directly from crude Escherichia coli lysates.

Amino Acid Sequence↗
PubMed1999

A method for computational combinatorial peptide design of inhibitors of Ras protein.

A computational combinatorial approach is proposed for the design of a peptide inhibitor of Ras protein. The procedure involves three steps. First, a 'Multiple Copy Simultaneous Search' identifies the location of specific functional groups on the Ras surface. This search method allowed us to identify an important binding surface consisting of two beta strands (residues 5-8 and 52-56), in addition to the well known Ras effector loop and switch II region. The two beta strands had not previously been reported to be involved in Ras-Raf interaction. Second, after constructing the peptide inhibitor chain based on the location of N-methylacetamide (NMA) minima, functional groups are selected and connected to the main chain Calpha atom. This step generates a number of possible peptides with different sequences on the Ras surface. Third, potential inhibitors are designed based on a sequence alignment of the peptides generated in the second step. This computational approach reproduces the conserved pattern of hydrophobic, hydrophilic and charged amino acids identified from the Ras effectors. The advantages and limitations of this approach are discussed.

Acetamides↗
PubMed2005

Design of a heterospecific, tetrameric, 21-residue miniprotein with mixed alpha/beta structure.

The study of short, autonomously folding peptides, or "miniproteins," is important for advancing our understanding of protein stability and folding specificity. Although many examples of synthetic alpha-helical structures are known, relatively few mixed alpha/beta structures have been successfully designed. Only one mixed-secondary structure oligomer, an alpha/beta homotetramer, has been reported thus far. In this report, we use structural analysis and computational design to convert this homotetramer into the smallest known alpha/beta-heterotetramer. Computational screening of many possible sequence/structure combinations led efficiently to the design of short, 21-residue peptides that fold cooperatively and autonomously into a specific complex in solution. A 1.95 A crystal structure reveals how steric complementarity and charge patterning encode heterospecificity. The first- and second-generation heterotetrameric miniproteins described here will be useful as simple models for the analysis of protein-protein interaction specificity and as structural platforms for the further elaboration of folding and function.

Amino Acid Sequence↗