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PubMed2002

Probing the mechanism of fusion in a two-dimensional computer simulation.

A two-dimensional (2D) model of lipid bilayers was developed and used to investigate a possible role of membrane lateral tension in membrane fusion. We found that an increase of lateral tension in contacting monolayers of 2D analogs of liposomes and planar membranes could cause not only hemifusion, but also complete fusion when internal pressure is introduced in the model. With a certain set of model parameters it was possible to induce hemifusion-like structural changes by a tension increase in only one of the two contacting bilayers. The effect of lysolipids was modeled as an insertion of a small number of extra molecules into the cis or trans side of the interacting bilayers at different stages of simulation. It was found that cis insertion arrests fusion and trans insertion has no inhibitory effect on fusion. The possibility of protein participation in tension-driven fusion was tested in simulation, with one of two model liposomes containing a number of structures capable of reducing the area occupied by them in the outer monolayer. It was found that condensation of these structures was sufficient to produce membrane reorganization similar to that observed in simulations with "protein-free" bilayers. These data support the hypothesis that changes in membrane lateral tension may be responsible for fusion in both model phospholipid membranes and in biological protein-mediated fusion.

Biophysical Phenomena↗
PubMed2002

Solution structure of a putative HIV1 immunogenic peptide: computer simulation of the principal CD4 binding domain of gp120.

A 15-residue segment within the principal CD4 binding domain of gp120 from HIV1 is a natural subject for vaccine development. Knowledge of a three-dimensional structure of this peptide in aqueous solution can in principle be used for pharmacophoric footprint identification. However, the peptide is resistant to structural characterization using nuclear magnetic resonance (NMR) due to aggregation properties. Here we examine the conformational properties of the peptide using molecular dynamics simulation. Three simulations were performed starting from widely different structures of the peptide determined by NMR in organic solvents. The three structures converge during the simulations to a common structure in both Cartesian and in backbone dihedral conformational space. Preliminary examination of the average three-dimensional structure identifies, after sequence threading, characteristics of potential use as a pharmacophoric footprint.

Binding Sites↗
PubMed1988

Computer simulation of cardiac pacing.

A mathematical model of the cardiac conduction system, including external pacemakers, has been developed. The heart is modeled as a network in which the impulse propagation is described by differential equations; several arrhythmia-generating mechanisms, such as modulated parasystole, reflection, macro and micro re-entry and block, can be simulated. Different kinds of pacemaker modes have been incorporated in the model, thus making it possible to simulate the interaction between the heart and the pacemaker. The model can be tuned by the user according to electrophysiological data so that pacemaker programs can be tested under different underlying conditions. During a simulation, the program generates ECG signals and pacemaker diagnostic diagrams. This model can be used for training and testing, and also as a support system when searching for the optimal pacing therapy for a particular patient.

Computer Simulation↗
PubMed1997

Computer simulation of time-gated transillumination and reflection of biological tissues and tissuelike phantoms.

A simulation technique is employed to explore the possibility of locating millimeter-sized objects, immersed in turbid media, from time-gated measurements of the transmitted or reflected light. The simulation results for tissuelike phantoms are compared to experimental transillumination data and excellent agreement is found. Simulations of time-gated reflection experiments show that it is possible to detect objects of 1 mm diameter. This may open new possibilities for medical diagnosis of breast cancer in an early stage.

Algorithms↗
PubMedDate not supplied

Computer simulation of portal venous shunting and other isolated hepatobiliary defects of the enterohepatic circulation of bile acids using a physiological pharmacokinetic model.

The effect of three isolated defects in the enterohepatic circulation of bile acids on the size and distribution of the bile acid pool, plasma bile acid levels and bile acid secretion into the intestine was simulated using a linear multicompartmental physiological pharmacokinetic model previously used to simulate these aspects of bile acid metabolism in healthy man. Stepwise increases in portal-systemic shunting (with a reciprocal decrease in hepatic blood flow) caused an exponential increase in systemic plasma concentrations of bile acids, but no other major changes in bile acid metabolism. When the effect of varying fractional hepatic extraction was simulated, it was found that the greater the fractional hepatic extraction, the greater the elevation observed for systemic plasma bile acid levels for a given degree of portal-systemic shunting. When total hepatic blood flow was restored to normal by simulating "arterialization," systemic plasma levels of bile acids decreased strikingly, yet remained elevated. For cholate with a fractional hepatic extraction of 0.9 and 100% portal-systemic shunting, arterialization caused a decrease from a 20-fold elevation to a 5-fold elevation. This simulation thus defined the effect of the presence of the portal venous system per se on plasma bile acid levels and also quantified the circulatory route by which substances reach the liver when portal-systemic shunting is present. An isolated defect in hepatic uptake of bile acids caused little change in overall bile acid metabolism other than modestly increased plasma levels. Loss of bile acid storage by the gallbladder caused the majority of the bile acid pool to move from the gallbladder compartments to the proximal small intestine during fasting but had little effect on the dynamics of the enterohepatic circulation during eating. The results of these novel simulations of isolated defects in bile acid transport should aid in the interpretation of the more complex changes in bile acid metabolism which are likely to occur in hepatic or biliary disease.

Bile Acids and Salts↗
PubMed2006

Structures of soluble amyloid oligomers from computer simulations.

Alzheimer's, Parkinson's, and Creutzfeldt-Jakob's neurodegenerative diseases are all linked with the assembly of normally soluble proteins into amyloid fibrils. Because of experimental limitations, structural characterization of the soluble oligomers, which form early in the process of fibrillogenesis and are cytotoxic, remains to be determined. In this article, we study the aggregation paths of seven chains of the shortest amyloid-forming peptide, using an activitated method and a reduced atomic representation. Our simulations show that disordered KFFE monomers ultimately form three distinct topologies of similar energy: amorphous oligomers, incomplete rings with beta-barrel character, and cross-beta-sheet structures with the meridional but not the equatorial X-ray fiber reflections. The simulations also shed light on the pathways from misfolded aggregates to fibrillar-like structures. They also underline the multiplicity of building blocks that can lead to the formation of the critical nucleus from which rapid growth of the fibril occurs.

Amyloid↗
PubMed2005

High pressure reveals that the stability of interdimeric contacts in the R- and T-state of HbA is influenced by allosteric effectors: Insights from computational simulations.

The molecular details of the mechanism of action of allosteric effectors on hemoglobin oxygen affinity are not clearly understood. The global allostery model proposed by Yonetani et al. suggests that the binding of allosteric effectors can take place both in the R and T states and that they influence oxygen affinity through inducing global tertiary changes in the subunits. Recently published high pressure studies yielded dissociation constants at atmospheric pressure that showed a stabilizing effect of heterotropic allosteric effectors on the dimer interface in the R state, and a more pronounced destabilizing effect in a T state model. In the present work, we report on computational modeling used to interpret the high pressure experimental data. We show structural changes in the hemoglobin interdimeric interfaces, indicative of a global tertiary structural change induced by the binding of allosteric effectors. We also show that the number of water molecules bound at the interface is significantly influenced by binding effectors in the T state in accordance with the experimental data. Our results suggest that the binding of effectors at definite sites leads to tertiary changes that propagate to the interfaces and results in overall structural re-organizations.

Allosteric Regulation↗
PubMed1988

Pancreatic islet discrimination of hexose anomers. I. Steady-state computer simulation.

Pancreatic islets detect glucose level by phosphorylating it and converting the glycolytic rate to a signal to secrete insulin. Insulin secretion is greater from the alpha- than from the beta-anomer when the D-glucose level is below 22 mM. D-mannose behaves similarly but at nearly twofold higher concentrations. Two explanations have been proposed: 1) glucokinase, which has the same anomeric preference, is the principal hexose phosphorylating enzyme and limits glycolytic rate. 2) Phosphofructokinase limits glycolysis and hexokinase is the principal enzyme phosphorylating hexose; hexosediphosphate activators of phosphofructokinase are more readily synthesized from alpha-anomers of hexose phosphates. We have simulated both alternatives with a detailed anomerically specific model of the hexose-metabolizing glycolytic enzymes. The pathway preference for alpha-anomer of both hexoses was adequately reproduced with anomerically active limiting glucokinase. The other mechanism did not reproduce the observed pathway preference.

Animals↗
PubMed1989

A computer simulation of T2 decay effects in echo planar imaging.

The effect of spatially variant T2 decay in echo planar images has been investigated. A simple, direct method to remove T2 effects, requiring no knowledge of actual T2 values, is also reported. The method is based on taking the geometric mean of two Hermitian symmetric data points before Fourier transformation.

Computer Simulation↗
PubMedDate not supplied

[Computer simulation of post-traumatic emergency states].

The traumatologist's automatic informational and retrieval system permits one to make a diagnosis of injuries in a patient and to have recommendations on their treatment, as well as to analyze injury-related nonspecific adaptation syndromes of the locomotor apparatus, which are laid into the system of informational models.

Computer Simulation↗