Computer-predicted theophylline kinetics.
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Computers↗
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Cutting edge: identification of novel T cell epitopes in Lol p5a by computational prediction.
Although atopic allergy affects </=20% of the total population, the relationship between the protein structure and immunogenic activity of the allergens is still largely unknown. We observed that group 5 grass allergens are characterized by repeated structural motifs. Using a new algorithm, TEPITOPE, we predicted promiscuous HLA-DR ligands within the repeated motifs of the Lol p5a allergen from rye grass. In vitro binding studies confirmed the promiscuous binding characteristics of these peptides. Moreover, most of the predicted ligands were novel T cell epitopes that were able to stimulate T cells from atopic patients. We generated a panel of Lol p5a-specific T cell clones, the majority of which recognized the peptides in a cross-reactive fashion. The computational prediction of DR ligands might thus allow the design of T cell epitopes with potential useful application in novel immunotherapy strategies.
Allergens↗
Computer prediction of left ventricular complicance throughout diastole in normal patients.
This study deals with the development of a computer program to predict instantaneous left ventricular complicance, as defined by the tangent modulus E, throughout diastole. Diastole is divided into discrete time intervals according to the major events which occur: the start of isovolumic relaxation (aortic valve closure), mitral valve opening, the point of minimum left ventricular pressure, the junction of the rapid and slow filling phases, the start of atrial systole, and the peak of the 'a' wave. Each interval is separated into subintervals. Over each subinterval two mechanisms are assumed to operate: myocardial relaxation or contraction producing a pressure change without an accompanying volume change, followed by explansion of the left ventricle at constant pressure. Although these mechanisms occur simultaneously in the intact heart, they are treated sequentially in a multistage computer program that employs the finite element technique to determine the displacements within a thick-walled ellipsoidal shell. The smaller the time interval between successive stages, the closer is the approximation to the actual continous process of myocardial relaxation, contraction, and distension. Diastolic determinants revealed in this investigation are the mechanical properties of the myocardium, the state variables of pressure and volume, and the control variables of wall thickness and cavity size. In isovolumic relaxation, the myocardium relaxes and the ventricular wall thickens to reduce intracavitary pressure. The relaxation process continues and intraventricular pressure falls to a minimum (0-point) while ventricular volume increases after mitral valve opening. In the succeeding phases, excluding atrial systole, ventricular filling pursues, the properties of the myocardium change, there is an increase in tone (possibly due to myocardial contraction), the wall thins and intraventricular pressure rises. Computer prediction shows that at the start of diastole the tangent modulus is approximately 6 times the enddiastolic value, and is nearly 0 at the onset of the slow filling phase. Tangant modulus is a useful index by which to distinguish normal from abnormal patients provided the characteristics of E as a function of time are recognized and compared throughout diastole.
Compliance↗
Correlation of crystallographically determined and computationally predicted hydrogen-bonded pairing configurations of nucleic acid bases.
Crystals of pairs of H-bonded nucleic acid bases are generally grown from nonaqueous solutions. We have been able to predict the H-bonded configuration of most of the base pairs in such crystals by using an empirical-potential function we recently developed for calculating the energetics of such interactions in chloroform solution. The following configurations were computationally predicted to predominate and are those observed in crystal structures: the Watson-Crick G.C configuration instead of two competing configurations; the Hoogsteen-type configurations for A.T, A.U, and A.br5U instead of Watson-Crick-type configurations; the Watson-Crick-type configurations for 2-aminopurine.br5U instead of the purine N3-type configuration; the Watson-Crick-type configurations for 8-bromo-2,6-diaminopurine.T instead of the Hoogsteen or purine-N3-type configurations; the syn-anti configuration for br8A.br8I instead of the anti-anti configuration; the Watson-Crick-type configurations for br8A.br5U instead of the Hoogsteen-type configurations; and the Hoogsteen-type configurations for me8A.T instead of the Watson-Crick configurations. In addition, the H-bonded base triplet br5U.2,6-diaminopurine.br5U was calculated to have Hoogsteen and Watson-Crick-type configurations but not the purine N3-type configuration. Apparently, lattice forces and chance nucleation of a minor base pairing configuration are not significant when the stability difference between the preferred and alternative configurations exceeds a relatively small value. In one case, in order to correctly predict the base pairing configuration in the crystal, it was necessary to include a contribution due to a C--H...O bond, suggesting that this type of H bond can make a significant contribution to base pair stability.
Base Composition↗
Computational prediction of eukaryotic protein-coding genes.
The human genome sequence is the book of our life. Buried in this large volume are our genes, which are scattered as small DNA fragments throughout the genome and comprise a small percentage of the total text. Finding these indistinct 'needles' in a vast genomic 'haystack' can be extremely challenging. In response to this challenge, computational prediction approaches have proliferated in recent years that predict the location and structure of genes. Here, I discuss these approaches and explain why they have become essential for the analyses of newly sequenced genomes.
Amino Acid Sequence↗
Computational prediction of solubilizers' effect on partitioning.
A computational model for the prediction of solubilizers' effect on drug partitioning has been developed. Membrane/water partitioning was evaluated by means of immobilized artificial membrane (IAM) chromatography. Four solubilizers were used to alter the partitioning in the IAM column. Two types of molecular descriptors were calculated: 2D descriptors using the MOE software and 3D descriptors using the Volsurf software. Structure-property relationships between each of the two types of descriptors and partitioning were established using partial least squares, projection to latent structures (PLS) statistics. Statistically significant relationships between the molecular descriptors and the IAM data were identified. Based on the 2D descriptors structure-property relationships R(2)Y=0. 99 and Q(2)=0.82-0.83 were obtained for some of the solubilizers. The most important descriptor was related to logP. For the Volsurf 3D descriptors models with R(2)Y=0.53-0.64 and Q(2)=0.40-0.54 were obtained using five descriptors. The present study showed that it is possible to predict partitioning of substances in an artificial phospholipid membrane, with or without the use of solubilizers.
Chromatography↗
Positional characterisation of false positives from computational prediction of human splice sites.
The performance of computational tools that can predict human splice sites are reviewed using a test set of EST-confirmed splice sites. The programs (namely HMMgene, NetGene2, HSPL, NNSPLICE, SpliceView and GeneID-3) differ from one another in the degree of discriminatory information used for prediction. The results indicate that, as expected, HMMgene and NetGene2 (which use global as well as local coding information and splice signals) followed by HSPL (which uses local coding information and splice signals) performed better than the other three programs (which use only splice signals). For the former three programs, one in every three false positive splice sites was predicted in the vicinity of true splice sites while only one in every 12 was expected to occur in such a region by chance. The persistence of this observation for programs (namely FEXH, GRAIL2, MZEF, GeneID-3, HMMgene and GENSCAN) that can predict all the potential exons (including optimal and sub-optimal) was assessed. In a high proportion (>50%) of the partially correct predicted exons, the incorrect exon ends were located in the vicinity of the real splice sites. Analysis of the distribution of proximal false positives indicated that the splice signals used by the algorithms are not strong enough to discriminate particularly those false predictions that occur within +/- 25 nt around the real sites. It is therefore suggested that specialised statistics that can discriminate real splice sites from proximal false positives be incorporated in gene prediction programs.
Algorithms↗
Computer prediction of congestion in the obstetric ward.
A computer system was developed to predict congestion of the obstetric ward in the near future. The admittance and stay in the obstetric ward of every registered patient are simulated based on the table of reservation and observed data of hospital stay, and from this the number of inpatients (occupied beds) is predicted. If the expected date of confinement of every obstetric patient is put into the computer and the information on patients who have already given birth is deleted, it is possible to obtain a reasonably accurate prediction.
Bed Occupancy↗
Multiscreen serum analysis of highly sensitized renal dialysis patients for antibodies toward public and private class I HLA determinants. Implications for computer-predicted acceptable and unacceptable donor mismatches in kidney transplantation.
A multiscreen serum analysis program has been developed that permits a determination of antibody specificity for the vast majority of highly sensitized patients awaiting transplantation. This program is based on a 2 x 2 table analysis of correlations between serum reactivity with an HLA-typed cell panel and incorporates two modifications. One implements the concept of public HLA determinants based on the serologic crossreactivity among class I HLA antigens. The other modification derives from the premise that most highly sensitized patients maintain the same PRA and antibody profiles over many months and even years. Monthly screening results for patients with persistent PRA values can therefore be combined for analysis. For 132 of 150 highly sensitized patients with greater than 50% PRA, this multiscreen serum analysis program yielded information about antibody specificity toward public and private class I HLA determinants. The vast majority of patients (108 of 112) with PRA values between 50 and 89% showed antibody specificity generally toward one, two, or three public markers and/or the more common private HLA-A,B antigens. For 24 of 38 patients with greater than 90% PRA, it was possible to define one or few HLA-specific antibodies. The primary objective of the multiscreen program was to develop an algorithm about computer-predicted acceptable and unacceptable donor HLA-A,B antigens for patients with preformed antibodies. A retrospective analysis of kidney transplants into 89 highly sensitized patients has demonstrated that allografts with unacceptable HLA-A,B mismatches had significantly lower actuarial survival rates than those with acceptable mismatches (P = 0.01). This was shown for both groups of 32 primary transplants (44% vs. 67% after 1 year) and 60 retransplants (50% vs. 68%). Also, serum creatinine levels were significantly higher in patients with unacceptable class I mismatches (3.0 vs. 8.4 mg% [P = 0.007] after 2 weeks; 3.9 vs. 9.1 mg% [P = 0.014] after 4 weeks). Histopathologic analysis of allograft tissue specimens from 47 transplant recipients revealed a significantly higher incidence of humoral rejection (P = 0.02), but not cellular rejection, in the unacceptable mismatch group. These results suggest that the multiscreen program can establish which donor HLA-A,B mismatches must be avoided in kidney transplantation for most highly sensitized patients. For 18 of 150 high PRA renal dialysis patients, the multiscreen program could not define HLA-specific antibody. Most patients had greater than 90% PRA, and many of their sera appeared to contain IgM type nonspecific lymphocytotoxins that could be inactivated by dithioerythreitol (DTE).(ABSTRACT TRUNCATED AT 400 WORDS)
Antibodies↗
Computer predictions of antigenic domains in human immunodeficiency virus-1 envelope glycoprotein: comparison with reported experimental data.
Computer analyses of amino acid sequences in the human immunodeficiency virus-1 (HIV-1) envelope glycoprotein revealed that antigenic domains in the viral protein can be predicted on the basis of the physical properties of amino acids in the polypeptide chain. Relatively high values of surface probability, flexibility, and hydrophilicity were used as markers for domains of putative antigenicity. Comparison of the computer-predicted antigenic domains in the HIV-1 envelope with those reported experimentally indicate that computer analyses are able to predict antigenic domains. This study shows the usefulness of computer programs for the prediction of the antigenic domains in the HIV-1 envelope protein.
Amino Acid Sequence↗
Computational predictions of stable 2D arrays of bidisperse particles.
We study computationally the stability of various 2D arrays of bidisperse mixtures of stabilized nanoparticles through a melting simulation employing the Metropolis algorithm for determining surface diffusion. In our previous work [Langmuir 2004, 20, 9408], we studied computationally the stability of bidispersed monolayers of thiol-stabilized gold nanoparticles with a size ratio (sigma) of 0.375. We found that interparticle forces were essential to stabilize the LS (the two-dimensional NaCl analogue) lattice at the experimentally determined surface coverage. In this paper, we extend our study to determine the conditions necessary to form stable LS(2), LS(4), and LS(6) lattices, which have yet to be observed. Using a simple design rule that involves matching the distances between either large-large particles and large-small particles or large-small particles and small-small particles to correspond to the respective potential minima leads to predictions for size ratios that will form each desired lattice, given other parameters characterizing the systems' physical properties. We predict and verify computationally LS(2), LS(4), and LS(6) lattices at relatively low surface coverages. Additional simulations show that the LS, LS(2), and LS(6) lattices are indeed stable structures at their predicted surface coverage, whereas the LS(4) lattice is a metastable structure; however, a modest increase in the surface coverage of the LS(4) lattice converts it to a stable rather than long-lived metastable structure. This study may be used as a guide for experimentalists in their search for these novel structures.
Journal Article↗
Computational prediction of microRNAs encoded in viral and other genomes.
We present an overview of selected computational methods for microRNA prediction. It is especially aimed at viral miRNA detection. As the number of microRNAs increases and the range of genomes encoding miRNAs expands, it seems that these small regulators have a more important role than has been previously thought. Most microRNAs have been detected by cloning and Northern blotting, but experimental methods are biased towards abundant microRNAs as well as being time-consuming. Computational detection methods must therefore be refined to serve as a faster, better, and more affordable method for microRNA detection. We also present data from a small study investigating the problems of computational miRNA prediction. Our findings suggest that the prediction of microRNA precursor candidates is fairly easy, while excluding false positives as well as exact prediction of the mature microRNA is hard. Finally, we discuss possible improvements to computational microRNA detection.
Journal Article↗
Computational predictions and experimental affinity distributions for a homovanillic acid molecularly imprinted polymer.
Density Functional Theory calculations have been used to select, among a set of chemicals traditionally used in the formulation of non-covalent molecularly imprinted polymers (MIPs), the best functional monomer and porogenic solvent for the construction of a recognition element for the dopamine metabolite homovanillic acid (HVA). Theoretical predictions were confirmed through batch binding assays and voltammetric detection. The computational method predicts that trifluoromethacrylic acid and toluene are the monomer and solvent rendering the highest stabilization energy for the pre-polymerization adducts. HVA-MIP prepared using this formulation gives rise to a binding isotherm that is accurately modelled by the Freundlich isotherm. The binding properties of this polymer were estimated using affinity distribution analysis. An apparent number of sites of 13 micromol g(-1) with an average affinity constant of 2 x 10(4) M(-1) was obtained in the concentration window studied.
Acrylates↗
Potassium channels: a computer prediction of structure and selectivity.
Model structures for the pore of the potassium channels Shaker and ROMK1 are predicted. The models arise from computer simulations and suggest reasons for the striking selectivity of these channels for K+ and the blocking of ROMK1 by internal Mg2+. The modelled structure of the Shaker pore is supported by mutagenesis data. The mutagenesis experiments indicate the side chains responsible for binding to blocking agents [tetraethylammonium (TEA) and charybdotoxin (CTX)] and the model has these side chains suitably oriented for binding. An aromatic K+ binding site part way down the pore is also predicted by the Shaker pore model.
Amino Acid Sequence↗
Computer prediction of antigenic and topogenic domains in HSV-1 and HSV-2 glycoprotein B (gB).
The envelope glycoprotein B (gB) coded for by the herpes simplex virus type 1 (HSV-1) UL27 gene is similar to the amino acid (aa) sequence of the gB coded by a homologous gene in HSV-2 DNA. The putative antigenic domains in HSV-1 and HSV-2 gB glycoproteins were analyzed on a comparative basis by suitable computer programs, which allowed the prediction of putative antigenic and topogenic domains. The computer-derived domains were compared to experimentally reported antigenic domains in HSV-1 gB glycoprotein. The computer-predicted antigenic domains in the HSV-1 gB glycoprotein matched well with the reported experimentally derived antigenic domains. The aa sequence of antigenic domain 1 was noted to resemble the amino acid sequence in ApoE that is involved in the attachment of this protein to LDL receptors. The clusters of hydrophobic aa domains are conserved in the two viral glycoproteins and are signals for transfer of the viral proteins through the cellular membrane.
Amino Acid Sequence↗
Design of new cognition enhancers: from computer prediction to synthesis and biological evaluation.
To discover new cognition enhancers, a set of virtually designed synthesizable compounds from different chemical series was investigated using two computer-aided approaches. One of the approaches is prediction of biological activity spectra for substances (PASS) and the second is prediction of toxicity, mutagenicity, and carcinogenicity (DEREK). To increase the probability of finding new chemical entities, we investigated a heterogeneous set of highly diverse chemicals including different types of heterocycles: five-membered (thiophenes, thiazoles, imidazoles, oxazoles, pyrroles), six-membered (pyridines, pyrimidines), seven-membered (diazepines, triazepines), fused five+six-membered heterocycles (indoles, benzothiazoles, purines, indolizines, neutral, mesoionic, and cationic azolopyridines). A database including 5494 structures of compounds was created. On the basis of the PASS and DEREK prediction results, eight compounds with the highest probability of cognition-enhancing effect were selected. The cognition-enhancing activity testing showed that all of the selected compounds had a pronounced antiamnesic effect and were found to reduce significantly scopolamine-induced amnesia of passive avoidance reflex (PAR). The action of compounds at doses of 1 and 10 mg/kg caused a statistically significant increase in latent time of reflex and in the number of animals, which did not enter the dark chamber when testing the PAR. Therefore, on the basis of computer prediction, new cognition-enhancing agents were discovered within the chemical series, in which this activity was not known previously.
Amnesia↗
Computer predictions of bone remodeling around porous-coated implants.
Computer simulations of bone remodeling in response to mechanical stresses can be used to understand normal growth and development of the skeleton or to predict the remodeling of bone in response to prosthetic devices. Using a previously derived bone maintenance theory, a technique for computing bone density distributions was applied to the proximal femur and tibia using two-dimensional, multiple-loading finite element models. The models initially represented solid, homogeneous structures. Using an iterative bone remodeling technique that relates bone apparent density to loading history, the internal distributions of apparent density and elastic modulus for the normal bones were predicted. The finite element models were then modified to represent bones in which porous-coated femoral surface replacements and tibial tray components had been implanted. The same iterative remodeling method was then applied to predict the distribution of bone around these components. The predicted bone density distributions for the natural femur and tibia agree with previously documented normal bone morphology. The predicted bone density distributions around various implanted prostheses were characteristic of the component under investigation and were consistent with clinical and experimental findings of other investigators. In the femoral head, stress shielding occurred underneath the metal surface replacement cup, resulting in lower densities in the femoral head. The addition of a central femoral cup fixation peg caused bone hypertrophy around the peg. In the tibia, the stress concentrations around the pegs also resulted in denser bone, with a concomitant decrease in bone density at more peripheral locations underneath the prosthetic tray. This remodeling technique has the potential to be an important tool in predicting the possible remodeling consequences of new implant design features.
Biomechanical Phenomena↗
Rapid computer prediction of total body water in fluid overload.
Using computer analysis of the early plasma arterial disappearance curve of tritiated water (HTO), we sought the fewest points and earliest times needed to predict the final volume of dilution, total body water (TBW). In ten anesthetized adult female dogs weighing 19.1 +/- 0.5 kg, with bilateral ureteral ligation, 500 muC HTO were given IV. Arterial blood samples were taken until equilibrium (3 hours), when the approximate equivalent of extracellular fluid (ECF), 4,000 ml of lactated Ringer's solution, was given IV within 1 hour. The next day, in the second phase of the study, 1,000 muC of HTO were given IV and arterial blood samples were taken at intervals up to equilibrium (5 hours). TBW at 3 hours after the first HTO infusion was 63.3 +/- 1.2% body weight. Using a curve-fitting Fortran program (CFIT), the arterial plasma HTO concentrations were fitted to one or two exponentials. Although initial TBW could be predicted from arterial plasma concentrations of HTO during 20 minutes after injection in normally hydrated dogs, values during 60 minutes were required for accurate prediction of TBW after infusion of 4 L of fluid. TBW in normal and fluid-loaded animals was predicted within 2.3 +/- 0.6% of the final HTO equilibrium (r = 0.987).
Animals↗