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PubMed1991

Särimner: a computer model of diabetes physiology for education of physicians and patients.

Often diabetic patients have developed their skills by some trial-and-error-like training over a long period of time. To minimize this inconvenience we have made a mathematical model to facilitate diabetes education. The model consists of a number of blocks involved in diabetes physiology: digestion, blood (transport), pancreas, injected insulin absorption, liver, muscles, kidneys, metabolism and insulin sensitivity. The model serves as a demonstration object and the user can change meals, exercise and injections and see the resulting blood glucose level. A more experienced user can search for further explanations of different phenomena deeper in the physiology of the model. The model does not solve any problem for the user, but creates a learning situation in which the user, led by his own curiosity, successively increases his experience of diabetes physiology. Särimner is implemented as an easy-to-use menu driven computer program for IBM PC-clones with Hercules, EGA or VGA graphics.

Adolescent↗
PubMed2006

Red fluorescent protein DsRed: parametrization of its chromophore as an amino acid residue for computer modeling in the OPLS-AA force field.

Topology of the neutral form of the DsRed fluorescent protein chromophore as a residue of [(4-cis)-2-[(1-cis)-4-amino-4-oxobutanimidoyl]-4-(4-hydroxybenzylidene)-5-oxo-4,5-dihydro-1H-imidazol-1-yl]acetic acid was calculated with OPLS-AA force field. Use of this topology and molecular dynamics simulation allows calculating the parameters of proteins that contain such residue in their polypeptide chains. The chromophore parameters were obtained by ab initio (RHF/6-31G**) quantum chemical calculations applying density functional theory (B3LYP). Using this chromophore, we have calculated the molecular dynamics trajectory of tetrameric fluorescent protein DsRed in solution at 300 K (4 nsec). Correctness of the chromophore parametrization was revealed by comparison of quantitative characteristics of the chromophore structure obtained from the molecular dynamic simulations of DsRed protein with the quantitative characteristics of the chromophore based on the crystallographic X-ray data of fluorescent protein DsRed (PDB ID: 1ZGO, 1G7K, and 1GGX), and also with the quantitative characteristics of the chromophore obtained by quantum chemical calculations. Inclusion of the neutral form of DsRed protein chromophore topology into the OPLS-AA force field yielded the extended force field OPLS-AA/DsRed. This force field can be used for molecular dynamics calculations of proteins containing the DsRed chromophore. The parameter set presented in this study can be applied for similar extension in any other force fields.

Algorithms↗
PubMed1994

Characterization of substrate UpA binding to RNase A--computer modelling and energetics approach.

In the past two decades RNase A has been the focus of diverse investigations in order to understand the nature of substrate binding and to know the mechanism of enzyme action. Although this system is reasonably well characterized from the view point of some of the binding sites, the details of interactions in the second base binding (B2) site is insufficient. Further, the nature of ligand-protein interaction is elucidated generally by studies on RNase A-substrate analog complexes (mainly with the help of X-ray crystallography). Hence, the details of interactions at atomic level arising due to substrates are inferred indirectly. In the present paper, the dinucleotide substrate UpA is fitted into the active site of RNase A. Several possible substrate conformations are investigated and the binding modes have been selected based on Contact Criteria. Thus identified RNase A-UpA complexes are energy minimized in coordinate space and are analysed in terms of conformations, energetics and interactions. The best possible ligand conformations for binding to RNase A are identified by experimentally known interactions and by the energetics. Upon binding of UpA to RNase A, the changes associated with protein back bone, side chains in general and at the binding sites in particular are described. Further, the detailed interactions between UpA and RNase A are characterized in terms of hydrogen bonds and energetics. An extensive study has helped in interpreting the diverse results obtained from a number of experiments and also in evaluating the extent of changes the protein and the substrate undergo in order to maximize their interactions.

Animals↗
PubMedDate not supplied

[Computer modeling in the study of mechanism of catalytic activity and the structure of active site of glutamine(asparagine)ase. I. Pharmacophore models of glutamine(asparagine)ase substrates].

Glutamine(asparagine)ase catalyses desamidation of both L-glutamine and L-asparagine, and their D-isomers. In this study the two-pharmacophore models of main enzyme substrates and their hydrolysed analogues were design. The received models reflect two stage of substrate interaction with the enzyme active site. These models allow to explain the wide substrate specificity of glutamine(asparagine)ase.

Amidohydrolases↗
PubMed1993

A computer model for analysis of fluid resuscitation.

Injuries involving massive blood loss, such as burns, combat wounds, and injuries resulting from car accidents, require fluid resuscitation. The risk involved in fluid therapy is overloading of the circulation, resulting in pulmonary edema which can lead to death. The risk of pulmonary edema may be eliminated by proper determination of maximal infusion volume and rate. Reabsorption of fluid from the extravascular compartment and infusion of fluid following blood loss results in reduction of the hematocrit. This is accompanied by an increase in the heart's preload and afterload. Coronary driving pressure and flow increase due to increased volume. However, because of the reduced hematocrit this increase in coronary flow may not be sufficient to compensate the myocardium, in terms of oxygen supply, for the increase in oxygen consumption. A model of the cardiovascular system, including an extravascular compartment, was designed to analyze the effects of fluid infusion on hemodynamic variables, cardiac oxygen balance, and the redistribution of fluid between intravascular and extravascular compartments. The results indicate that edema is not the only possible adverse effect of overloading the cardiovascular system with fluid. The simulation demonstrated that in certain cases the heart's oxygen balance can become negative. Limiting the rate of infusion can reduce this risk.

Animals↗
PubMed2001

A computer model to simulate family history of breast/ovarian cancer in BRCA1 mutation carriers.

The BRCA1 gene and its relationship to family history of breast/ovarian cancer are difficult to study in a population because of practical and ethical issues. The paucity of information on BRCA1 in the general population was a major theme in a recent review of genetic testing in Canada. We develop a simulation model to mimic genetic inheritance and cancer incidence in the family of someone with a germline BRCA1 mutation. Given someone's age and family structure, our model simulates his or her family history in three steps: (1) determine which family members have the mutation, (2) determine the ages of family members and (3) determine which family members have breast/ovarian cancer. Each step involves random variation. Some parameters in our model are estimated using local (British Columbia, Canada) population data. The breast/ovarian cancer risk associated with BRCA1 mutations is estimated using values published in the literature. An example is provided to illustrate the model's application. The model incorporates results from genetics, demography and epidemiology, but requires several additional assumptions. Research to address these assumptions is recommended.

Adult↗
PubMed1998

Architecture of the sugar binding sites in carbohydrate binding proteins--a computer modeling study.

Different sugars, Gal, GalNAc and Man were docked at the monosaccharide binding sites of Erythrina corallodenron (EcorL), peanut lectin (PNA), Lathyrus ochrus (LOLI), and pea lectin (PSL). To study the lectin-carbohydrate interactions, in the complexes, the hydroxymethyl group in Man and Gal favors, gg and gt conformations respectively, and is the dominant recognition determination. The monosaccharide binding site in lectins that are specific to Gal/GalNAc is wider due to the additional amino acid residues in loop D as compared to that in lectins specific to Man/Glc, and affects the hydrogen bonds of the sugar involving residues from loop D, but not its orientation in the binding site. The invariant amino acid residues Asp from loop A, and Asn and an aromatic residue (Phe or Tyr) in loop C provides the basic architecture to recognize the common features in C4 epimers. The invariant Gly in loop B together with one or two residues in the variable region of loop D/A holds the sugar tightly at both ends. Loss of any one of these hydrogen bonds leads to weak interaction. While the subtle variations in the sequence and conformation of peptide fragment that resulted due to the size and location of gaps present in amino acid sequence in the neighborhood of the sugar binding site of loop D/A seems to discriminate the binding of sugars which differ at C4 atom (galacto and gluco configurations). The variations at loop B are important in discriminating Gal and GalNAc binding. The present study thus provides a structural basis for the observed specificities of legume lectins which uses the same four invariant residues for binding. These studies also bring out the information that is important for the design/engineering of proteins with the desired carbohydrate specificity.

Acetylgalactosamine↗
PubMed2006

Broca's area and inflectional morphology: evidence from broca's aphasia and computer modeling.

In a series of articles Ullman (2001, 2004; Ullman et al., 1997) has proposed that regular inflection is critically subserved by Broca's area. This suggestion is motivated by the finding that English speaking Broca's aphasics show selective deficits with regular inflection. Here we argue that this proposal does not hold cross-linguistically but is based on a confound between inflectional suffix and regularity that is specific to the English language. We present data from two experimental studies of participle inflection with 13 German and 12 Dutch Broca's aphasics. None of these aphasic speakers are selectively impaired for regular inflection but instead most of them show selective deficits with irregular inflection. These data suggest that a selective regular deficit is not a characteristic of Broca's aphasia across languages, and that Broca's area is not critically involved in regular inflection. To investigate the nature and localization of the processes underlying inflection we present a connectionist neural network model that accounts for the deficits of the German aphasic speakers. The model implements the view that the inflection of all verb types is based on a single mechanism with multiple representations that emerge from experience-dependent brain development. We show that global damage to this model results in a selective deficit for irregular inflection that is comparable to that of the German aphasic speakers. This finding suggests that a selective impairment of irregular participles as observed by German and Dutch aphasic speakers does not presuppose two distinctly localized mechanisms or processes that can be selectively affected by brain damage.

Adult↗
PubMed2000

Estimating the probability for a protein to have a new fold: A statistical computational model.

Structural genomics aims to solve a large number of protein structures that represent the protein space. Currently an exhaustive solution for all structures seems prohibitively expensive, so the challenge is to define a relatively small set of proteins with new, currently unknown folds. This paper presents a method that assigns each protein with a probability of having an unsolved fold. The method makes extensive use of protomap, a sequence-based classification, and scop, a structure-based classification. According to protomap, the protein space encodes the relationship among proteins as a graph whose vertices correspond to 13,354 clusters of proteins. A representative fold for a cluster with at least one solved protein is determined after superposition of all scop (release 1.37) folds onto protomap clusters. Distances within the protomap graph are computed from each representative fold to the neighboring folds. The distribution of these distances is used to create a statistical model for distances among those folds that are already known and those that have yet to be discovered. The distribution of distances for solved/unsolved proteins is significantly different. This difference makes it possible to use Bayes' rule to derive a statistical estimate that any protein has a yet undetermined fold. Proteins that score the highest probability to represent a new fold constitute the target list for structural determination. Our predicted probabilities for unsolved proteins correlate very well with the proportion of new folds among recently solved structures (new scop 1.39 records) that are disjoint from our original training set.

Amino Acid Sequence↗
PubMed1990

A computer model of antenatal care: relationship between the distribution of obstetric risk factors in simulated cases and in a real population.

The main purpose of antenatal care is to identify risk factors for the fetus. A number of systems have been described in which positive factors are summed to produce an overall risk score for the individual woman. In the present study a computer simulation of a population of pregnant women has been used to examine the use of Bayes theorem to calculate obstetric risk scores. The findings of the computer simulation have been compared with those in a real obstetric population (774 primigravidae; 930 multigravidae). A number of observations have been made which may be of considerable practical significance: (1) in the population as a whole the distribution of risk scores is skewed; most women have a low score while relatively few subjects have high scores; (2) a minimum number of risk factors must be present simultaneously for the risk in an individual to consistently exceed the overall population risk; this number is 4 in primigravidae and 5 in multigravidae; (3) the relationship between the number of risk factors and overall risk does not follow a straight line. The computer simulation provides a test bed in which various assumptions can be examined, such as the effect of removing or redefining given risk factors.

Bayes Theorem↗
PubMed1994

A computational model of the auditory periphery for speech and hearing research. I. Ascending path.

A dual analog/digital model of the ascending path through the entire auditory periphery is described. The analog representation consists of the concatenation of electrical circuit submodels for (a) the diffraction of the external ear system; (b) the propagation through the concha and auditory canal; (c) the transmission through the middle ear; (d) the basilar membrane motion and cochlear hydrodynamics; (e) the fast motile mechanism of the outer hair cells; and (f) the neural transduction process of the inner hair cells. Time-domain numerical solutions are obtained by applying the technique of wave digital filtering onto the resulting analog circuit. The present version of the model reproduces the sound pressure gain at the eardrum for lateral sound incidence, the vibration characteristics of the stapes, and the low-frequency attenuation provided by the stapedial muscle. Source elements in the cochlear module provide level-dependent basilar membrane tuning curves leading to dynamic compression of input signals near the characteristic frequency/place. The output is the tonotopic distribution of firing activity in the auditory nerve. A companion article addresses the modeling of the descending paths [C. Giguère and P. C. Woodland, J. Acoust, Soc. Am. 94, 343-349 (1993)].

Auditory Pathways↗
PubMed1997

Computer modelling of the receptor-binding domains of VEGF and PIGF.

Models of the platelet-derived growth factor (PDGF)-like domains of vascular endothelial growth factor (VEGF) and placenta growth factor (PIGF) were built based on their homology to PDGF. These domains contain most of the determinants for receptor binding. The sequences of these proteins exhibit limited but significant homology to that of platelet-derived growth factor (PDGF), a member of the cystine knot growth factor family. The eight cysteine residues that are involved in intra- and interchain disulphide bonds are conserved. Two high affinity receptors for VEGF have been identified, only one of which binds PIGF. The models presented here are consistent with results that show that VEGF receptor binding is mediated by charged residues in the loops. A comparison of the models suggests that the difference in receptor-binding specificity between VEGF and PIGF may be due to differences in the distribution of positively charged residues and the exposure of hydrophobic residues in the loops.

Amino Acid Sequence↗
PubMed2004

Computer modeling of polyleucine-based coiled coil dimers in a realistic membrane environment: insight into helix-helix interactions in membrane proteins.

Simulated annealing was performed to model parallel dimers of alpha-helical transmembrane peptides with the sequence L(11)XL(12), predicting left-handed coiled coil geometry in all cases. Insertion of peptides containing threonine, asparagine, alanine, phenylalanine, and leucine in position 12 into realistic model membranes showed these structures were stable for 20 ns of molecular dynamics simulation time. Threonine could participate in intermolecular hydrogen bonds, but predominantly formed hydrogen bonds to the backbone of the helix it resided on. These hydrogen bonds, although infrequent, appeared to promote closer association of polyleucine helices. Asparagine participated in multiple, rapidly fluctuating intermolecular and intramolecular hydrogen bonds, and may have slightly destabilized optimum van der Waals packing in favor of optimum hydrogen bonding. Coordinated rotations of transmembrane helices about their axes were observed, indicating helices may rotate around one another during the folding of membrane proteins or other processes. These rotations were inhibited by phenylalanine, suggesting a role for bulky residues in modulating membrane protein dynamics.

Amino Acids↗
PubMed1993

Computer model of membrane current and intracellular Ca2+ flux in the isolated guinea pig ventricular myocyte.

This paper presents the equations and responses of a mathematical model that simulates the transmembrane current and intracellular concentrations of Ca2+ ([Ca2+]), Na+ ([Na+]), and K+ ([K+]) of an isolated guinea pig myocyte. The structure of the model is closely related to the formulation of DiFrancesco and Noble (9). Quantitative values are based on a large number of experimental constraints, taken from the literature on isolated myocytes as well as our own experimental studies, that describe the properties of individual channels and integrated responses of whole cells under a variety of conditions. The model was constructed as a homeostatic system. The equilibrium of the model corresponds to the resting potential and intracellular ionic concentrations of unstimulated myocytes. The model generates deviations from equilibrium corresponding to the behavior of cells after stimulation of action potentials at different rates, blockade of Na-K-adenosinetriphosphatase (ATPase), reduction in extracellular [K+], and injection of constant depolarizing current. Simulations from the model suggest that changes in myoplasmic [Ca2+] at different stimulation rates, the generation of restitution and postextrasystolic potentiation, and the development of intracellular [Ca2+] oscillations arise simply from different interactions between uptake of Ca2+ into the sarcoplasmic reticulum via the Ca(2+)-ATPase, Ca(2+)-induced Ca2+ release of Ca2+ into the myoplasm, flux between regions of uptake and release, and leakage between sarcoplasmic reticulum and myoplasm. The model also demonstrates that a wide variety of basic electrophysiological responses of the isolated guinea pig myocyte can be simulated with quantitative precision by a single set of equations based on experimentally measured transmembrane current and intracellular [Ca2+] and [Na+].

Action Potentials↗
PubMed1994

A desk-top computer model of the circulatory system for heart assistance simulation: effect of an LVAD on energetic relationships inside the left ventricle.

The study of the interaction between a pneumatic left ventricle assist device (LVAD), driven with different control strategies, and the cardiovascular system is the subject of this paper. It is performed by a modular numerical model of the cardiovascular system connected to a numerical model of the LVAD. The circulatory system is simulated by a lumped parameter numerical model. The ventricle is represented by a time-varying elastance model to reproduce the Starling law of the heart. The effect of the LVAD on the cardiovascular system is evaluated, on the left ventricle alone, by an open-loop circuit consisting of the models of the ventricle, the LVAD and the arterial tree. The analysis is performed in terms of energy variables (such as external work and oxygen consumption and cardiac mechanical efficiency versus control strategy. The LVAD is driven by different control strategies: a fixed heart rate (with different delays from the onset of the natural ventricle contraction) and a variable heart rate.

Cardiovascular Physiological Phenomena↗
PubMed2006

Ab initio computational modeling of loops in G-protein-coupled receptors: lessons from the crystal structure of rhodopsin.

With the help of the crystal structure of rhodopsin an ab initio method has been developed to calculate the three-dimensional structure of the loops that connect the transmembrane helices (TMHs). The goal of this procedure is to calculate the loop structures in other G-protein coupled receptors (GPCRs) for which only model coordinates of the TMHs are available. To mimic this situation a construct of rhodopsin was used that only includes the experimental coordinates of the TMHs while the rest of the structure, including the terminal domains, has been removed. To calculate the structure of the loops a method was designed based on Monte Carlo (MC) simulations which use a temperature annealing protocol, and a scaled collective variables (SCV) technique with proper structural constraints. Because only part of the protein is used in the calculations the usual approach of modeling loops, which consists of finding a single, lowest energy conformation of the system, is abandoned because such a single structure may not be a representative member of the native ensemble. Instead, the method was designed to generate structural ensembles from which the single lowest free energy ensemble is identified as representative of the native folding of the loop. To find the native ensemble a successive series of SCV-MC simulations are carried out to allow the loops to undergo structural changes in a controlled manner. To increase the chances of finding the native funnel for the loop, some of the SCV-MC simulations are carried out at elevated temperatures. The native ensemble can be identified by an MC search starting from any conformation already in the native funnel. The hypothesis is that native structures are trapped in the conformational space because of the high-energy barriers that surround the native funnel. The existence of such ensembles is demonstrated by generating multiple copies of the loops from their crystal structures in rhodopsin and carrying out an extended SCV-MC search. For the extracellular loops e1 and e3, and the intracellular loop i1 that were used in this work, the procedure resulted in dense clusters of structures with Calpha-RMSD approximately 0.5 angstroms. To test the predictive power of the method the crystal structure of each loop was replaced by its extended conformations. For e1 and i1 the procedure identifies native clusters with Calpha-RMSD approximately 0.5 angstroms and good structural overlap of the side chains; for e3, two clusters were found with Calpha-RMSD approximately 1.1 angstroms each, but with poor overlap of the side chains. Further searching led to a single cluster with lower Calpha-RMSD but higher energy than the two previous clusters. This discrepancy was found to be due to the missing elements in the constructs available from experiment for use in the calculations. Because this problem will likely appear whenever parts of the structural information are missing, possible solutions are discussed.

Computer Simulation↗
PubMed1975

The role of myocardial membrane leakage channels in the production of fibrillation: studies with an analog computer model.

The conditions under which automatic activity and fibrillation can occur were studied through the use of an analog model. Parameters (transmembrane active and passive properties) were established from biological data of mammalian myocardial fibers. The definition of instability of membrane potential can be given by the following functions of inward and outward steady state current (I) to voltage relationships of the membrane. 1) With decreasing angle between the tangent of the slope of the Iout and (-1) Iin, instability increases at constant potential. 2) Instability is also a function of the membrane potential as related to peak inward current (nonsteady state) at a given angle. 3) Maximum peak inward current and minimum angle produced such instability as to cause fibrillation. The most likely explanation is that automaticity and/or fibrillation is induced by leakage currents which change the normal current/voltage relatiosnhip in the described manner. The membrane leakage currents could be specific to sodium or unspecific.

Biological Transport, Active↗