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At least 109 records · Page 6Linked to original sources
PubMed2005

Computational design of combinatorial peptide library for modulating protein-protein interactions.

Screening phage-displayed combinatorial peptide library is an effective approach for discovery of peptide modulators for protein-protein interactions. However, as peptide length increases, the chance of finding active peptides in a finite size library diminishes. To increase the likelihood of finding peptides that bind to a protein, we develop statistical potential for computational construction of biased combinatorial antibody-like peptide libraries. Based on the alpha shapes of antibody-antigen complexes, we developed an empirical pair potential for antigen-antibody interactions that depends on local packing. We validate this potential and show that it can successfully discriminate the native interface peptides from a simulated library of 10,000 random peptides for 34 antigen-antibody complexes. In addition, we show that it can successfully recognize the native binding surface patch among all possible surface patches taken from either the antibody or the antigen for seven antibody-antigen protein complexes contained in the CAPRI (Critical Assessment of Predicted Interactions) dataset. We then develop a Weighted Amino Acid Residue sequence Generator (WAARG) for design of biased peptide library. When compared with a random peptide library, WAARG libraries contain more native-like binding peptides at a significantly smaller size. Our method can be used to construct peptide library for screening of antibody variants with improved specificity and affinity to a target antigen. It can also be used for screening of antibody-like antagonist peptides modulating other protein-protein interactions.

Amino Acid Sequence↗
PubMed1997

Computational design of a bypass graft that minimizes wall shear stress gradients in the region of the distal anastomosis.

PURPOSE: Recent experimental and theoretic studies show that large wall shear stress gradients characterize disturbed flow patterns associated with the location of myointimal hyperplasia, atheroma, or both. Graft-to-artery anastomoses that minimize wall shear stress gradients may reduce the degree of myointimal development and the propensity for thrombosis. This study analyzes the distribution of distal anastomotic wall shear stress gradients for conventional geometries and for the optimized geometry assuming idealized merging of the graft with the artery. METHODS: A validated computational fluid dynamics program was used to solve the transient three-dimensional partial differential equations and auxiliary equations that describe laminar incompressible blood flow. Time-averaged wall shear stresses and wall shear stress gradients were calculated for three distal graft-artery anastomoses: a standard end-to-side, a Taylor patch, and an optimized geometry. The latter was obtained iteratively by minimizing the local wall shear stress gradients and was analyzed under resting and exercise inflow waveforms. RESULTS: Both the standard and Taylor patch anastomoses have relatively high wall shear stress gradients in the regions of the toe and heel. For all flow inputs studied nonuniform hemodynamics in the optimized graft design are largely eliminated, and the time-averaged wall shear stress gradients are greatly reduced throughout the anastomotic zone. At resting flow the Taylor patch produces slightly lower wall shear stress gradients in the anastomotic region than the standard end-to-side anastomosis. The optimized design reduces wall shear stress gradients to almost one half of that of the standard and Taylor patch geometries. At exercise flow wall shear stress gradients almost triple in the standard anastomosis and increase approximately 30% in the Taylor patch. In contrast, the geometrically optimized design is basically independent of the type of flow input waveform in terms of time-averaged wall shear stress gradients and disturbed flow patterns. CONCLUSION: This study demonstrates that it is possible to design a terminal graft geometry for an end-to-side anastomosis that significantly reduces wall shear stress gradients. If the wall shear stress gradient is confirmed to be a major hemodynamic determinant of intimal hyperplasia and restenosis, these results may point to the design of optimal bypass graft geometries.

Algorithms↗
PubMed1996

Computer design and syntheses of antiulcer compounds. 1st communication: N-[3-[3-(1-piperidinomethyl)phenoxy]propyl]amines and benzamides.

Aiming to develop new antiulcer agents, a quantitative structure-activity relationship (QSAR) study on in vitro (pA2) and in vivo histamine H2-receptor antagonistic activity of a series of N-[3-[3-(1-piperidinomethyl)phenoxy]propyl]amines was carried out using the OASIS computer system. The results showed that pA2 increases with the decrease (increase) of electron donor (acceptor) properties of molecules, particularly at the NH-reaction site. The finding is consistent with the assumption for an increase of histamine H2-receptor activity of the antagonists with their ability to form H-bonds with the receptor through NH groups. The correlations with hydrophobicity and related topological indices are consistent with the hypothesis that logP should indirectly reflect receptor interactions. In addition a series of N-[3-[3-(1-piperidinomethyl)phenoxy]propyl]benzamides are synthesized. The theoretically predicted in vitro activities of these compounds were found to be in accordance with in vivo tests (percent of inhibition of gastric juice and acid output [mEq/H+/3 h]).

Animals↗
PubMed2004

Computational design of water-soluble analogues of the potassium channel KcsA.

Although the interiors of membrane and water-soluble proteins are similar in their physicochemical properties, membrane proteins differ in having larger fractions of hydrophobic residues on their exteriors. Thus, it should be possible to water-solubilize membrane proteins by mutating their lipid-contacting side chains to more polar groups. Here, a computational approach was used to generate water-soluble variants of the potassium channel KcsA. As a probe of the correctness of the fold, the proteins contain an agitoxin2 binding site from a mammalian homologue of the channel. The resulting proteins express in high yield in Escherichia coli and share the intended functional and structural properties with KcsA, including secondary structure, tetrameric quaternary structure, and tight specific binding to both agitoxin2 and a small molecule channel blocker.

Amino Acid Sequence↗
PubMed2001

Computational design and nonlinear dynamics of a recurrent network model of the primary visual cortex.

Recurrent interactions in the primary visual cortex make its output a complex nonlinear transform of its input. This transform serves preattentive visual segmentation, that is, autonomously processing visual inputs to give outputs that selectively emphasize certain features for segmentation. An analytical understanding of the nonlinear dynamics of the recurrent neural circuit is essential to harness its computational power. We derive requirements on the neural architecture, components, and connection weights of a biologically plausible model of the cortex such that region segmentation, figure-ground segregation, and contour enhancement can be achieved simultaneously. In addition, we analyze the conditions governing neural oscillations, illusory contours, and the absence of visual hallucinations. Many of our analytical techniques can be applied to other recurrent networks with translation-invariant neural and connection structures.

Animals↗
PubMed1979

Computer design synthesis of a below knee-Syme prosthesis.

A detailed design synthesis analysis of the BK Syme prosthesis is provided, to determine the socket's cutout orientation size and shape, cutout fillet shape, socket wall thickness distribution and the reinforced fiber distribution in the socket wall, for a minimally stressed structurally safe lightweight prosthesis. For analysis purpose, the most adverse socket loading is obtained at the push-off stage of gait; this loading is idealised as an axial in-plane loading on the bottom edge of the circular cylindrical socket shell whose top edge is considered fixed. Finite element stress analysis of the socket shell (with uniform and graded wall thickness) are performed for various orientations of the cutout and for various types of corner fillets. A lateral cutout with a streamline fillet is recommended. The wall material (i.e., thickness) distribution is determined so as to minimise the stresses, while ensuring that the wall material's stress limits are not exceeded. For such a maximally-stressed lightweight socket shell, the panels in the neighbourhood of the cutout are checked to ensure that they do not buckle under their acquired stresses. A fiber-reinforced laminated composite socket shell is also analysed, to recommend optimum variables in orientations and densities of reinforcing fibers.

Ankle↗
PubMed2001

Conversion of a maltose receptor into a zinc biosensor by computational design.

We have demonstrated that it is possible to radically change the specificity of maltose binding protein by converting it into a zinc sensor using a rational design approach. In this new molecular sensor, zinc binding is transduced into a readily detected fluorescence signal by use of an engineered conformational coupling mechanism linking ligand binding to reporter group response. An iterative progressive design strategy led to the construction of variants with increased zinc affinity by combining binding sites, optimizing the primary coordination sphere, and exploiting conformational equilibria. Intermediates in the design series show that the adaptive process involves both introduction and optimization of new functions and removal of adverse vestigial interactions. The latter demonstrates the importance of the rational design approach in uncovering cryptic phenomena in protein function, which cannot be revealed by the study of naturally evolved systems.

Alanine↗
PubMed2006

Computational design and experimental evaluation of glycosyltransferase mutants: engineering of a blood type B galactosyltransferase with enhanced glucosyltransferase activity.

Glycosyltransferases are an enormous and diverse class of enzyme encompassing 1% of all sequenced genomes. They catalyze the transfer of a monosaccharide from an activated donor such as a sugar-nucleotide to an acceptor molecule. Though the primary sequences of glycosyltransferases have little homology, X-ray structural studies on glycosyltransferases have revealed that there are two main folds and that the orientation of the sugar donors with respect to the folds is highly conserved. It seems that glycosyltransferases have evolved diversified specificities toward donor sugars by changing the amino acids around the monosaccharide moiety without altering the orientation of the nucleotide moiety. In this study, we designed new glycosyltransferases with altered donor specificities by use of a novel empirical model called the Epimer Propensity Index (EPI). The EPI was constructed using 221 carbohydrate-protein complex structures in the Protein Data Bank with either galactose or glucose in the complex. The blood type B synthesizing glycosyltransferase GTB, a galactosyltransferase was our target enzyme. Two GTB mutants designed to exhibit enhanced glucosyltransferase activity were cloned, expressed and characterized experimentally. The predicted GTB mutants, Ser185Asn and Ser185Cys, exhibited 4.3- and 4.8-fold elevations in k(cat)/K(m) for UDP-Glc relative to that of wild-type enzyme.

Amino Acid Substitution↗
PubMed1997

Structure-based drug design: computational advances.

Structure-based computational methods continue to enhance progress in the discovery and refinement of therapeutic agents. Several such methods and their applications are described. These include molecular visualization and molecular modeling, docking, fragment methods, 3-D database techniques, and free-energy perturbation. Related issues that are discussed include the use of simplified potential energy functions and the determination of the positions of tightly bound waters. Strengths and weaknesses of the various methods are described.

Algorithms↗
PubMed2004

Use of computer-designed group II introns to disrupt Escherichia coli DExH/D-box protein and DNA helicase genes.

Mobile group II introns are site-specific retroelements that use a novel mobility mechanism in which the excised intron RNA inserts directly into a DNA target site and is then reverse transcribed by the associated intron-encoded protein. Because the DNA target site is recognized primarily by base-pairing of the intron RNA with only a small number of positions recognized by the protein, it has been possible to develop group II introns into a new type of gene targeting vector ("targetron"), which can be reprogrammed to insert into desired DNA targets simply by modifying the intron RNA. Here, we used databases of retargeted Lactococcus lactis Ll.LtrB group II introns and a compilation of nucleotide frequencies at active target sites to develop an algorithm that predicts optimal Ll.LtrB intron-insertion sites and designs primers for modifying the intron to insert into those sites. In a test of the algorithm, we designed one or two targetrons to disrupt each of 28 Escherichia coli genes encoding DExH/D-box and DNA helicase-related proteins and tested for the desired disruptants by PCR screening of 100 colonies. In 21 cases, we obtained disruptions at frequencies of 1-80% without selection, and in six other cases, where disruptants were not identified in the initial PCR screen, we readily obtained specific disruptions by using the same targetrons with a retrotransposition-activated selectable marker. Only one DExH/D-box protein gene, secA, which was known to be essential, did not give viable disruptants. The apparent dispensability of DExH/D-box proteins in E.coli contrasts with the situation in yeast, where the majority of such proteins are essential. The methods developed here should permit the rapid and efficient disruption of any bacterial gene, the computational analysis provides new insight into group II intron target site recognition, and the set of E.coli DExH/D-box protein and DNA helicase disruptants should be useful for analyzing the function of these proteins.

Algorithms↗
PubMed1993

Computer-designed expert systems for breast cytology diagnosis.

Three expert systems have been developed to diagnose from nine scalar values visually assigned to epithelial cells obtained by breast fine needle aspiration. These expert systems achieved up to 0.98 sensitivity and 0.97 specificity. When applied to 804 breast masses, the clinical sensitivity was 0.98 and specificity was 0.93 (exclusive of the 0.04 unsatisfactory aspirates). Cancers can be missed physically during the aspiration process; thus, some clinically suspicious masses were biopsied despite benign cytology. This contributed to the difference between the expert system and clinical specificities.

Algorithms↗
PubMed2005

Osteogenic differentiation of mesenchymal progenitor cells in computer designed fibrin-polymer-ceramic scaffolds manufactured by fused deposition modeling.

Biomimetic scaffolds offer great potentials in the development of bone analogs for tissue engineering. The studies presented in this paper focus specifically on the osteogenic potential of the novel PCL/CaP matrices and its degradation behavior. Biodegradable Polymer-ceramic Scaffolds were fabricated using the solid free form fabrication technology: Fused Deposition Modeling (FDM). The scaffold architecture was characterized by a honeycomb-like design and a complete interconnectivity of the pores. Human mesenchymal stem cells (MSCs) were seeded together with fibrin glue into PCL/CaP scaffolds and cultured in vitro for periods of up to eight weeks. Cellular adhesion, proliferation and osteogenic differentiation were assessed in these constructs using a range of histological and microscopic techniques. In additional experiments, degradation was assessed by measuring mass loss, diameter change, molecular weight change and by scanning electron micrographs. MSCs were able to adhere, migrate, and differentiate along the osteogenic lineage with in these scaffolds. The PCL/CaP scaffolds showed up to 27 fold increased degradation of compared to PCL scaffolds.

Biodegradation, Environmental↗
PubMed1998

Newly designed computer controlled knee-ankle-foot orthosis (Intelligent Orthosis).

The authors have developed a knee-ankle-foot orthosis with a joint unit that controls knee movements using a microcomputer (Intelligent Orthosis). The Intelligent Orthosis was applied to normal subjects and patients, and gait analysis was performed. In the gait cycle, the ratio of the stance phase to the swing phase was less in gait with the knee locked using a knee-ankle-foot orthosis than in gait without an orthosis or gait with the knee controlled by a microcomputer. The ratio of the stance phase to the swing phase between controlled gait and normal gait was similar. For normal subjects the activity of the tibialis anterior was markedly increased from the heel-off phase to the swing phase in locked gait. The muscle activities of the lower limb were lower in controlled gait than in locked gait. The ground reaction force in locked gait showed spikes immediately after heel-contact in the vertical component, and unusual patterns were observed at heel-contact in the sagittal and lateral component. Therefore, compared to locked gait, gait with the Intelligent Orthosis is smooth and close to normal gait from the viewpoint of biomechanics. Even in patients with muscle weakness of the quadriceps, control of the knee joint using the Intelligent Orthosis resulted in a more smooth gait with low muscle discharge.

Adult↗
PubMed1998

Improved stability and yield of a Fv-toxin fusion protein by computer design and protein engineering of the Fv.

The conversion of the anti-mesothelin monoclonal antibody K1 to a single-chain Fv (scFv) that is fused to a truncated form of Pseudomonas exotoxin A (PE) results in a fusion protein (immunotoxin) that is unstable and refolds very inefficiently. We have devised a method that identifies candidate residues in the framework region of K1 Fv that, when mutated, improved the yield and stability of the protein. The method works by initially aligning the framework sequences of K1 VH and VL with those of other scFvs that are stable and give a good yield as immunotoxins. Then we assigned a character to each residue that indicates its state of exposure based on the known crystal structures of Fabs. This identifies residues that are not compatible with their environment in the folded state of the protein. Next we calculated the frequencies of different amino acids for each position of the Fvs based on the available sequence database. This identifies residues that are not commonly present in the conserved positions. If these residues are compatible with their exposure profile they are left unaltered. Otherwise, they are identified as candidate residues for mutation. We identified two such residues in the VH (T82 and A85) and two in the VL (H36 and V60) of K1 that did not seem appropriate for their respective positions. By mutating these residues in K1 into those that occur most commonly in the sequence database or in stable scFvs, we significantly improved the stability and yield of the K1 scFv immunotoxins. By making single and combined mutations we assessed the relative contribution of mutations at these four sites towards the stability and yield of K1 scFv immunotoxins. The method we devised is probably general and can be used to improve other scFvs.

Amino Acid Sequence↗