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PubMed2002

Accurate computer-based design of a new backbone conformation in the second turn of protein L.

The rational design of loops and turns is a key step towards creating proteins with new functions. We used a computational design procedure to create new backbone conformations in the second turn of protein L. The Protein Data Bank was searched for alternative turn conformations, and sequences optimal for these turns in the context of protein L were identified using a Monte Carlo search procedure and an energy function that favors close packing. Two variants containing 12 and 14 mutations were found to be as stable as wild-type protein L. The crystal structure of one of the variants has been solved at a resolution of 1.9 A, and the backbone conformation in the second turn is remarkably close to that of the in silico model (1.1 A RMSD) while it differs significantly from that of wild-type protein L (the turn residues are displaced by an average of 7.2 A). The folding rates of the redesigned proteins are greater than that of the wild-type protein and in contrast to wild-type protein L the second beta-turn appears to be formed at the rate limiting step in folding.

Amino Acid Sequence↗
PubMed2005

Electrostatics in computational protein design.

Catalytic activity and protein-protein recognition have proven to be significant challenges for computational protein design. Electrostatic interactions are crucial for these and other protein functions, and therefore accurate modeling of electrostatics is necessary for successfully advancing protein design into the realm of protein function. This review focuses on recent progress in modeling electrostatic interactions in computational protein design, with particular emphasis on continuum models.

Computer Simulation↗
PubMed2004

Fabrication of tissue engineered tympanic membrane patches using computer-aided design and injection molding.

OBJECTIVES/HYPOTHESIS: The goal of the current study was to use computer-aided design and injection molding technologies to tissue engineer precisely shaped cartilage in the shape of butterfly tympanic membrane patches out of chondrocyte-seeded calcium alginate gels. METHODS: Molds were designed on SolidWorks 2000 and built out of acrylonitrile butadiene styrene (ABS) using fused deposition modeling (FDM). Tympanic membrane patches were fabricated using bovine articular chondrocytes seeded at 50 x 10 cells/mL in 2% calcium alginate gels. Molded patches were cultured in vitro for up to 10 weeks and assessed biochemically, morphologically, and histologically. RESULTS: Unmolded patches demonstrated outstanding dimensional fidelity, with a volumetric precision of at least 3 microL, and maintained their shape well for up to 10 weeks of in vitro culture. Glycosaminoglycan and collagen content increased steadily over 10 weeks in culture, demonstrating continual deposition of new extracellular matrix consistent with new tissue development. CONCLUSIONS: The use of computer-aided design and injection molding technologies allows for the fabrication of very small, precisely shaped chondrocyte-seeded calcium alginate structures that faithfully maintain their shape during in vitro culture. In vitro fabrication of tympanic membrane patches with a precisely controlled geometry may have the potential to provide a minimally invasive alternative to traditional methods for the repair of chronic tympanic membrane perforations.

Analysis of Variance↗
PubMed2005

The computer-aided design and rapid prototyping fabrication of removable partial denture frameworks.

This study explores the application of computer-aided design and manufacture (CAD/CAM) to the process of electronically surveying a scanned dental cast as a prior stage to producing a sacrificial pattern for a removable partial denture (RPD) metal alloy framework. These are designed to retain artificial replacement teeth in the oral cavity. A cast produced from an impression of a patient's mouth was digitally scanned and the data converted to a three-dimensional computer file that could be read by the computer-aided design (CAD) software. Analysis and preparation were carried out in the digital environment according to established dental principles. The CAD software was then used to design the framework and generate a standard triangulation language (STL) file in preparation for its manufacture using rapid prototyping (RP) methods. Several RP methods were subsequently used to produce sacrificial patterns, which were then cast in a chromium-cobalt alloy using conventional methods and assessed for accuracy of fit. This work demonstrates that CAD/CAM techniques can be used for electronic dental cast analysis, preparation, and design of RPD frameworks. It also demonstrates that RP-produced patterns may be successfully cast using conventional methods and that the resulting frameworks can provide a satisfactory fit.

Computer-Aided Design↗
PubMed1989

Computer-aided design in wheelchair seating.

This paper describes the integration of computer-aided design (CAD) with the design and fabrication of wheelchair seats. The use of CAD during the design phase permits personal seating for adult and pediatric clientele through a series of standard manufactured seating components. The advent of CAD has permitted the creation of databases of detailed 3-D wheelchair structures that are commercially available, in addition to most standard modular seating components. Direct on-screen manipulation of these components on any selected wheelchair structure is through user-friendly software. When using CAD, structural and physical limitations can be foreseen and taken into consideration during the routine initial fitting on an adjustable simulation fitting chair. The end product is a dimensioned drawing of the seating arrangement as it is positioned in the wheelchair structure. The seating components are manufactured from this drawing. The CAD system permits seating specialists to simulate a client's seating arrangement on the wheelchair in order to determine a functional position before the fabrication phase. Essentially, the CAD software is used as a simulation tool for creating functional seating units. It is also a design tool that allows access through a database to dimensional information about commercial seating products and seating products developed through the use of the CAD system.

Computer Graphics↗
PubMed2006

Computer-aided design of promising photochemical alkoxy radical precursors.

A computer-aided design of alkoxyl radical precursors is performed. The new precursors should combine the advantages of N-alkoxypyridine-2(1H)thiones (less reactive radicals) and N-alkoxythiazole-2(3H)thiones (stable with respect to daylight). Additionally, the radical liberation process should be initiated by light with a wavelength of around 350 nm. To find promising compounds, 18 test candidates were obtained by a systematic variation of the parent compound N-alkoxythiazole-2(3H)thione. The properties of the test molecules were computed by a protocol that was already successfully used to rationalize the photochemical behavior of N-alkoxypyridine-2(1H)thiones and N-alkoxythiazole-2(3H)thiones. The computations identify two promising new compounds. For N-methoxy-(1,3)dihydro-[1,3]azaphosphole-2-thione (6a), they predict that the fragmentation process will be initiated by an absorption at 348 nm. An analysis of its fragmentation process indicates that the free excess energy of the resulting radicals should more resemble the situation found for N-alkoxypyridine-2(1H)thiones. For N-methoxy-(1,3)dihydro-pyrrole-2-thione (3a), the excitation energy is somewhat higher (330 nm), but the computed fragmentation paths again indicate that the remaining excess energy of the released radicals is quite favorable. The test molecules also contained the experimentally well-known N-methoxypyridine-2(1H)one (1b). For this molecule, our computed data rationalizes nicely the experimental findings.

Alcohols↗
PubMed1988

[Computer aided design of anticancer drugs].

The recent advances in computer science and technology enabled us to use computer for drug-design. Calculation of structural features of drugs and modeling of biomacromolecules by means of 3D-computer graphics afford a new approach to comprehend a molecular interaction which is important for drug action. As target molecules for anticancer drug, DNA structure can be elucidated and drug-DNA complex model can be constructed to give further insight for drug design. For example, complex of DNA double helix and bleomycin was built and by conjunction with other complex model such as mitomycin C, anthramycin, and netropsin it would be able to design a base sequence specific DNA-groove binding molecule. In addition, DNA is also a target molecule for antibiotics which intercalate between base pairs. Rational design of intercalator and groove binder thus would lead a novel anticancer drug. On the other hand, combination of the fruitful results of molecular biology and gene engineering with computer technology, will give a detail of protein structure which is one of most desired information for designing novel drugs.

Antineoplastic Agents↗
PubMed2006

Emergence of protein fold families through rational design.

Diverse proteins with similar structures are grouped into families of homologs and analogs, if their sequence similarity is higher or lower, respectively, than 20%-30%. It was suggested that protein homologs and analogs originate from a common ancestor and diverge in their distinct evolutionary time scales, emerging as a consequence of the physical properties of the protein sequence space. Although a number of studies have determined key signatures of protein family organization, the sequence-structure factors that differentiate the two evolution-related protein families remain unknown. Here, we stipulate that subtle structural changes, which appear due to accumulating mutations in the homologous families, lead to distinct packing of the protein core and, thus, novel compositions of core residues. The latter process leads to the formation of distinct families of homologs. We propose that such differentiation results in the formation of analogous families. To test our postulate, we developed a molecular modeling and design toolkit, Medusa, to computationally design protein sequences that correspond to the same fold family. We find that analogous proteins emerge when a backbone structure deviates only 1-2 angstroms root-mean-square deviation from the original structure. For close homologs, core residues are highly conserved. However, when the overall sequence similarity drops to approximately 25%-30%, the composition of core residues starts to diverge, thereby forming novel families of protein homologs. This direct observation of the formation of protein homologs within a specific fold family supports our hypothesis. The conservation of amino acids in designed sequences recapitulates that of the naturally occurring sequences, thereby validating our computational design methodology.

Computational Biology↗
PubMedDate not supplied

Touchable objects: attributes applied to the design of computer input devices.

Among many important attributes, designers often seek to create products that are comfortable both in the sense of avoiding discomfort and providing a positive sense of comfort. Another way of looking at the design of hand-held products is to consider what attributes make a product enjoyable to touch, rather than just comfortable or uncomfortable. A series of focus discussions investigated the qualities of objects that are enjoyable to touch. Persons were asked to bring in one or two objects that said to them, "Touch me" and "Keep touching me". Discussion with the participants discerned their motivations for selecting the touchable objects. Observations noted the objects' sizes, weights, shapes, surfaces, and colours. This research about qualities of touchable objects influenced the designs of new designs of trackballs for computer navigation. Further hypothesis supposes that the attributes of touchable objects are based on human experience over time with nature.

Adult↗
PubMed2006

New algorithms and an in silico benchmark for computational enzyme design.

The creation of novel enzymes capable of catalyzing any desired chemical reaction is a grand challenge for computational protein design. Here we describe two new algorithms for enzyme design that employ hashing techniques to allow searching through large numbers of protein scaffolds for optimal catalytic site placement. We also describe an in silico benchmark, based on the recapitulation of the active sites of native enzymes, that allows rapid evaluation and testing of enzyme design methodologies. In the benchmark test, which consists of designing sites for each of 10 different chemical reactions in backbone scaffolds derived from 10 enzymes catalyzing the reactions, the new methods succeed in identifying the native site in the native scaffold and ranking it within the top five designs for six of the 10 reactions. The new methods can be directly applied to the design of new enzymes, and the benchmark provides a powerful in silico test for guiding improvements in computational enzyme design.

Algorithms↗
PubMed1994

The effects of computer interface design on human postural dynamics.

The main objective of this study was to examine the effects of human-computer interface design on postural dynamics, i.e., changes in working postures and postural discomfort exhibited by operators of the computer-based remote bar coding (RBC) system. In addition, the effects of different work/rest schedules on postural dynamics were evaluated. Twelve subjects participated in the laboratory experiment, which consisted of twelve scenarios utilizing two cognitive task requirement factors, i.e., (1) information presentation mode, defined through the letter image preview on the computer screen (none or one preview image); and (2) the information processing mode, defined through the specific keying method (key all characters or key 5 digits only). The third experimental factor was the work/rest schedule (50 min work/10 min break, 2 h of work/15 min break, or flexible schedule). The results showed that requirements of human-computer interface design significantly affected the operators' postural dynamics. It was concluded that not only the physical, organizational, or psychosocial work environment characteristics, but also the cognitive task characteristics are important for assessment of postural effects in the VDT work. The relationship between interface design, mental workload and postural dynamics should be carefully considered in future studies aimed at optimizing the human-computer data entry tasks.

Adult↗
PubMed1984

Computer software design for pediatric practice. A modular approach.

Practical applications for using computers in everyday medical practice have not kept pace with the technical developments that now make this tool available to the pediatric practitioner. A modular approach to user-developed applications software is presented as a model for computerizing the pediatric office. Benefits have included lower cost, greater data reliability and validity, standardization of office and medical procedures, and automation of jobs formerly requiring much personnel time. Some patient services have improved, and other new services have become possible, through the application of computer software designed in accordance with our practice philosophy.

Computers↗
PubMed2005

Hydroxyl groups in the (beta)beta sandwich of metallo-beta-lactamases favor enzyme activity: a computational protein design study.

Metallo-beta-lactamases challenge antimicrobial therapies by their ability to hydrolyze and inactivate a broad spectrum of beta-lactam antibiotics. The potential of these enzymes to acquire enhanced catalytic efficiency through mutation is of great concern. Here, we explore the potential of computational protein design to predict mutants of the imipenemase IMP-1 that modulate the catalytic efficiency of the enzyme against a range of substrates. Focusing on the four amino acid positions 69, 121, 218, and 262, we carried out a number of design calculations. Two mutant enzymes were predicted: the single mutant S262A and the double mutant F218Y-S262A. Compared to IMP-1, the single mutant (S262A) results in the loss of a hydroxyl group and the double mutant (F218Y-S262A) results in a hydroxyl transfer from position 262 to position 218. The presence of both hydroxyl groups at positions 218 and 262 was tested by examining the mutant F218Y. Kinetic constants of IMP-1, the two computationally designed mutants (S262A and F218Y-S262A), and the hydroxyl addition mutant (F218Y) were determined with seven substrates. Catalytic efficiencies are highest for the enzyme with both hydroxyl groups (F218Y) and lowest for the enzyme lacking both hydroxyl groups (S262A). The catalytic efficiencies of the two enzymes with one hydroxyl group each are intermediate, with the F218Y-S262A double mutant exhibiting enhanced hydrolysis of nitrocefin, cephalothin, and cefotaxime relative to IMP-1.

Bacteroides fragilis↗
PubMed2004

Sulfonamide-based acyclic and conformationally constrained MMP inhibitors: from computer-assisted design to nanomolar compounds.

The present account relates to our studies in the computer assisted design and synthesis of acyclic and cyclic MMP inhibitors. Our early efforts focused on the preparation of cyclopropane and tetrahydrofuran-based mimics of batimastat which were not active. The discovery of subnanomolar sulfonamide-based acyclic inhibitors instigated the design of novel target compounds. Thus, with the help of a fully automated and reliable docking program, we embarked on the design and synthesis of enantiopure inhibitors incorporating cyclic scaffolds. This ultimately led to compounds exhibiting inhibitory activities in the nanomolar range. Interestingly, the qualitative ranking prediction was found to be in good agreement with the observed activities.

Animals↗
PubMed1987

Computer-aided design of a prosthetic socket for an above-knee amputee.

A computer-aided design process for fabricating the rectified cast for an above-knee prosthetic socket is described. The methodology for collecting the parameters required for the computer analysis is discussed. The input variables include the unloaded shape of the residual limb, the mechanical properties of the soft tissues that comprise the limb, and the surface loading that deforms the tissue. The technologies that have been developed to ascertain these parameters are presented, and the clinical experience of using the computer-generated shape is presented.

Artificial Limbs↗
PubMed2006

Combinatorial methods for small-molecule placement in computational enzyme design.

The incorporation of small-molecule transition state structures into protein design calculations poses special challenges because of the need to represent the added translational, rotational, and conformational freedoms within an already difficult optimization problem. Successful approaches to computational enzyme design have focused on catalytic side-chain contacts to guide placement of small molecules in active sites. We describe a process for modeling small molecules in enzyme design calculations that extends previously described methods, allowing favorable small-molecule positions and conformations to be explored simultaneously with sequence optimization. Because all current computational enzyme design methods rely heavily on sampling of possible active site geometries from discrete conformational states, we tested the effects of discretization parameters on calculation results. Rotational and translational step sizes as well as side-chain library types were varied in a series of computational tests designed to identify native-like binding contacts in three natural systems. We find that conformational parameters, especially the type of rotamer library used, significantly affect the ability of design calculations to recover native binding-site geometries. We describe the construction and use of a crystallographic conformer library and find that it more reliably captures active-site geometries than traditional rotamer libraries in the systems tested.

Catalytic Domain↗
PubMedDate not supplied

Molecular simulation and drug design.

Computer simulation techniques have become a major tool in the analysis of biomolecular properties and behaviour. These techniques are used extensively in drug and protein design projects, because they can provide information that is complementary to experimental data. Molecular mechanics methods such as energy minimization and molecular dynamics are among the most commonly used simulation techniques for the study of biomolecules. We present here a brief description of some molecular mechanics methods and a few applications examples for biomacromolecules and biomolecular complexes.

Computer Simulation↗