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PubMed2001

Computational modelling of inhibitor binding to human thrombin.

Thrombin is an essential protein involved in blood clot formation and an important clinical target, since disturbances of the coagulation process cause serious cardiovascular diseases such as thrombosis. Here we evaluate the performance of a molecular dynamics based method for predicting the binding affinities of different types of human thrombin inhibitors. For a series of eight ligands the method ranks their relative affinities reasonably well. The binding free energy difference between high and low affinity representatives in the test set is quantitatively reproduced, as well as the stereospecificity for a chiral inhibitor. The original parametrisation of this linear interaction energy method requires the addition of a constant energy term in the case of thrombin. This yields a mean unsigned error of 0.68 kcal/mol for the absolute binding free energies. This type of approach is also useful for elucidating three-dimensional structure-activity relationships in terms of microscopic interactions of the ligands with the solvated enzyme.

Antithrombins↗
PubMedDate not supplied

Reduction of triceps muscle force after shortening of the distal humerus: a computational model.

Bone deficiency resulting in shortening of the distal humerus may occur after fractures, treatment of nonunions, or revision of total elbow arthroplasty. A biomechanical model of the triceps muscle and tendon was used to investigate the effect of distal humeral shortening on triceps force production. The analysis indicated that shortening of the distal humerus primarily influences the media head of the triceps, which contributes most to elbow extension strength in extended elbow positions. In a posture of 30 degrees elbow flexion, shortening the distal humerus by 1, 2, and 3 cm reduced the extension strength by 17%, 40%, and 63%, respectively. At 90 degrees of flexion, strength was reduced by 11%, 15%, and 21%, respectively. This result suggests that shortening the humerus by 1 cm may be well tolerated, but shortening by 2 or more cm may cause a significant reduction in triceps force. This would be particularly important in patients requiring terminal extension strength for weight bearing.

Arm↗
PubMed2002

The computational modeling of analogy-making.

Our ability to see a particular object or situation in one context as being 'the same as' another object or situation in another context is the essence of analogy-making. It encompasses our ability to explain new concepts in terms of already-familiar ones, to emphasize particular aspects of situations, to generalize, to characterize, to explain or describe new phenomena, to serve as a basis for how to act in unfamiliar surroundings, and to understand many types of humor. Within this framework, the importance of analogy-making in modeling cognition becomes clear.

Journal Article↗
PubMedDate not supplied

Threshold fluctuations on temporally modulated backgrounds: a possible physiological explanation based upon a recent computational model.

When a temporally fluctuating background is rapidly modulated (e.g. 30 Hz), the threshold variation of a superimposed flash (the probe) is approximately sinusoidal and in phase with the stimulus. But, with low rates of sinusoidal modulation (e.g. 1 Hz), the threshold variation is distinctly nonsinusoidal in shape. The bases of these aspects of the data, as well as an unmodulated, dc, threshold elevation, are poorly understood. Here 30-Hz and 1-Hz conditions are simulated using a new model of light adaptation (Wilson, 1997). By assuming that the OFF pathway is twice as sensitive as the ON pathway, the model correctly captured the key aspects of both conditions. The results suggest that the 1-Hz data are mediated by a mixture of ON and OFF pathways while the 30-Hz data are largely mediated by the OFF pathway. The probe thresholds on the 30-Hz background appear approximately sinusoidal and approximately in phase with the background stimulus. A number of factors contribute to this deceptively simple observation.

Adaptation, Ocular↗
PubMed2004

A computational model relating structure and reactivity in enantioselective oxidations of secondary alcohols by (-)-sparteine-Pd(II) complexes.

The key interactions responsible for the unique reactivity of (-)-sparteine-PdX(2) complexes (X = chloride, acetate) in the enantioselective oxidation of secondary alcohols have been elucidated using quantum mechanics (B3LYP DFT with the PBF polarizable continuum solvent model). From examining many possible pathways, we find the mechanism involves: (1) substitution of the alcohol in place of an X-group, (2) deprotonation of the bound alcohol by the deposed anion and free sparteine, (3) beta-hydride elimination through a four-coordinate transition state in which the second anion is displaced but tightly associated, (4) replacement of the ketone product with the associated anion. The enantioselectivities observed under base-rich reaction conditions follow directly from calculated energies of diastereomeric beta-hydride elimination transition states incorporating (R) and (S) substrates. This relationship reveals an important role of the anion, namely to communicate the steric interaction of the ligand on one side of the Pd(II) square plane and the substrate on the other side. When no anion is included, no enantioselectivity is predicted. Locating these transition states in different solvents shows that higher dielectrics stabilize the charge separation between the anion and metal and draw the anion farther into solution. Thus, the solvent influences the barrier height (rate) and selectivity of the oxidation.

Alcohols↗
PubMed2003

Computational models for predicting the binding affinities of ligands for the wild-type androgen receptor and a mutated variant associated with human prostate cancer.

In the present study, values of the binding energy (BE) were calculated for the rat androgen receptor on a data set of 25 steroidal and nonsteroidal compounds for which published values of the observed binding affinity (K(i)) are available. A correlation between BE and pK(i) was evident (r(2) = 0.50) for the entire data set and became more pronounced when the steroids and nonsteroids were plotted separately (r(2) congruent with 0.76). Including BE as an additional descriptor to supplement the default steric-electrostatic descriptors in comparative molecular field analysis dramatically improved the predictive ability of the resulting three-dimensional quantitative structure-activity relationship models. We also demonstrate that the observed loss in ligand specificity between the wild-type (wt) AR and the T877A mutant AR associated with androgen-independent prostate cancer is reflected in decreased BE values (i.e., higher binding affinity) for the antiandrogen pharmaceutical hydroxyflutamide and for several nonandrogenic endogenous steroids, most notably cortisol, corticosterone, 17beta-estradiol, progesterone, and 17alpha-hydroxyprogesterone.

Amino Acid Substitution↗
PubMed1994

Computational modeling and elementary process analysis in visual word recognition.

An attempt is made to isolate the assumptions that make a connectionist approach to visual word recognition distinctive. These include the commitment to distributed representations, the claim that there is no distinction between lexical and nonlexical systems in the naming task, and the claim that it is possible to map from orthography to meaning without using localized representations. It is argued that merely demonstrating that a network model can perform these tasks is not sufficient and that a detailed theory of how the network performs its tasks must accompany the simulation, because a simulation is not equivalent to an explanation. It is argued that further progress requires detailed modeling and experimental study of the elementary processes assumed to be involved in networks and that it is premature to dismiss alternative models of lexical access such as serial search models.

Humans↗
PubMed2000

The role of computational models in neuropsychological investigations of language: reply to Ruml and Caramazza (2000).

W. Ruml and A. Caramazza's (2000) analysis of the model of normal and aphasic lexical access proposed by G. S. Dell, M. F. Schwartz, N. Martin, E. M. Saffran, and D. A. Gagnon (1997) is completely at odds with current practice concerning the use of models in psychology. An evaluation of Dell et al.'s original claims using Ruml and Caramazza's model parameters sustains these claims in all respects.

Aphasia↗
PubMed2004

Neighbourhood density, word frequency, and spelling-sound regularity effects in naming: similarities and differences between skilled readers and the Dual Route Cascaded Computational model.

An experiment with skilled readers and a series of simulations with the Dual Route Cascaded model (Coltheart, Rastle, Perry, Langdon, & Ziegler, 2001) investigated the joint effects of stimulus quality and Neighbourhood Density (N) in nonword naming. Neighbourhood Density and stimulus quality yielded additive effects on RT for skilled readers whereas the model produced an interaction between these factors. A further set of simulations show that DRC also produces an interaction between stimulus quality and (1) word frequency, (2) spelling-sound regularity, and, (3) nonword letter length. None of these three factors interact with stimulus quality in performance by skilled readers. It is suggested that DRC's assumption of cascaded processing throughout represents a central problem. A proposal as to how the model can be modified to accommodate these and other problematic data is discussed.

Humans↗
PubMed2007

3D computation modelling of the influence of cytokine secretion on Th-cell development suggests that negative selection (inhibition of Th1 cells) is more effective than positive selection by IL-4 for Th2 cell dominance.

Th-cell development has been suggested to include selective mechanisms in which certain cytokines select either Th1 or Th2 cells to proliferate and grow. The selective theory is based on the observation that Th2 cells secrete IL-4, a cytokine that promotes Th2 development, whereas Th1 cells secrete interferon-gamma (IFN-gamma) that favours Th1 development, and both positive and negative selective influences have been suggested to operate. In this study, we investigate the role of autocrine secretion and utilization of IL-4 by Th2 cells and address the question of whether an activated Th2 cell can be positively selected by IL-4 secreted from other Th2 cells. We present a spatial three dimensional (3D) modelling approach to simulate the interaction between the IL-4 ligand and its IL-4 receptors expressed on discrete IL-4 secreting cells. The simulations, based on existing experimental data on the IL-4 receptor-ligand system, illustrate how Th-cell development is highly dependent on the distance between cells that are communicating. The model suggests that a single Th2 cell is likely to communicate with possible target cells within a range of approximately 100 microm and that an activated Th2 cell manages to fill most of its own IL-4 receptors, even at a low secretion rate. The predictions made by the model suggest that negative selection against Th1 cells is more effective than positive selection by IL-4 for promoting Th2 dominance.

Animals↗
PubMed2006

cis-[PtBr2{PPh2(4-catechol)}2]: synthesis, crystal structure, and computational modelling of its binding to nanocrystalline TiO2.

The complex cis-[PtBr(2){PPh(2)(4-catechol)}(2)]1 has been synthesized by cleavage of the four methyl groups from cis-[PtCl(2){PPh(2)(4-veratrole)}(2)] using BBr(3), followed by work-up in the presence of excess bromide. An X-ray crystal structure of 1.(ethanol)(2) confirms that the two catechol rings are adjacent to each other and approximately parallel, and therefore well structured to act as double bidentate ligands for adjacent metal atoms on the surface of a nanocrystal. The crystal packing of 1.(ethanol)(2) involves intermolecular hydrogen-bonding interactions and a parallel fourfold phenyl embrace between PPh(2) moieties. Density functional calculations have demonstrated that conformational variability of the aryl rings in cis-[PtBr(2){PPh(2)(4-catechol)}(2)] is energetically feasible, and two conformations of cis-[PtBr(2){PPh(2)(4-catechol)}(2)] as a complex ligand for Ti atoms on the various surfaces of the anatase and rutile structures of TiO(2) have been assessed for geometrical commensurability. Three structural models for adsorbates of cis-[PtBr(2){PPh(2)(4-catechol)}(2)] on TiO(2) are developed for anatase (110), anatase (101), and rutile (001).

Journal Article↗
PubMed1997

Maintenance of chaos in a computational model of a thermal pulse combustor.

The dynamics of a thermal pulse combustor model are examined. It is found that, as a parameter related to the fuel flow rate is varied, the combustor will undergo a transition from periodic pulsing to chaotic pulsing to a chaotic transient leading to flameout. Results from the numerical model are compared to those obtained from a laboratory-scale thermal pulse combustor. Finally the technique of maintenance (or anticontrol) of chaos is successfully applied to the model, with the result that the operation of the combustor can be continued well into the flameout regime. (c) 1997 American Institute of Physics.

Journal Article↗
PubMed2005

Computational model of the cAMP-mediated sensory response and calcium-dependent adaptation in vertebrate olfactory receptor neurons.

We develop a mechanistic mathematical model of the G-protein coupled signaling pathway responsible for generating current responses in frog olfactory receptor neurons. The model incorporates descriptions of ligand-receptor interaction, intracellular transduction events involving the second messenger cAMP, effector ion-channel activity, and calcium-mediated feedback steps. We parameterized the model with respect to suction pipette current recordings from single cells stimulated with multiple odor concentrations. The proposed model accurately predicts the receptor-current response of the neuron to brief and prolonged odorant exposure and is able to produce the adaptation observed under repeated or sustained stimulation.

Adaptation, Physiological↗
PubMed2002

Computational model of the modulation of gene expression following DNA damage.

High linear energy transfer (LET) radiation, such as heavy ions or neutrons, has an increased biological effectiveness compared to X rays for gene mutation, genomic instability, and carcinogenesis. In the traditional paradigm, mutations or chromosomal aberrations are causative of late effects. However, in recent years experimental evidence has demonstrated the important role of the description of the modification of gene expression by radiation in understanding the mechanisms of radiation action. In this report, approaches are discussed to the mathematical description of mRNA and protein expression kinetics following DNA damage. Several hypotheses for models of radiation modulation of protein expression are discussed including possible non-linear processes that evolve from the linear dose responses that follow the initial DNA damage produced by radiation.

Cell Division↗