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PubMed1991

Computer simulation of the binding of saframycin A to d (GATGCATC)2.

The binding of Saframycin A to the octanucleotide duplex d(GATGCATC)2 was investigated using molecular dynamics. For covalent binding at N2 of the central guanine, only the R configuration at the alkylating carbon (C7) was permitted for B DNA and the 3' direction in the minor groove was preferred by 50.6 kcal/mol. The dihydroquinone form of saframycin A gave stronger binding than the quinone, in agreement with the literature. Addition of solvent and counterions made no significant change in the geometry model. The proposed mechanism of DNA alkylation, involving iminium ion intermediates from the dihydroquinone or quinone, was investigated by modeling these species. They gave models with good net binding enthalpies, and C7 was in close proximity to N2 of guanine. The noncovalent binding of saframycin A and its dihydroquinone in the vicinity of guanine also was favorable in the 3' direction.

Antibiotics, Antineoplastic↗

PubMed1990

Serial dependency in the discharge pattern of dorsal spinocerebellar tract neurons: a computer simulation analysis.

We have developed a model in order to analyze the factors eventually responsible for the strong negative serial dependency between successive interspike intervals in the discharge of the Dorsal Spinocerebellar Tract (DSCT) neurons. This dependency is reflected, phenomenologically, by short intervals followed by long ones and, quantitatively, by the first order correlation coefficient (R1-2); which can be lower than -.6 (Jansen, Nicolaysen & Rudjord, 1966; Kröller and Grüsser, 1982). We have found that the lowest values of R1-2 are always related with model parameter values which were very similar to those obtained experimentally. It was observed that EPSP amplitude distribution plays an important role in the discharge patterns of the DSCT neurons. There is one fiber that elicits EPSPs greater than 6 mV, which is responsible for the genesis of the short intervals in the discharge. Long intervals are determined basically by a suprathreshold depolarization and the afterhyperpolarization processes.

Action Potentials↗

PubMed1986

Estimating the power of a proposed linkage study: a practical computer simulation approach.

I describe a simulation method to estimate the power to detect linkage given a set of pedigrees of known structure and for which family history data may be available. This method can be applied to autosomal and X-linked dominant diseases; depending on the pedigrees under consideration, it will often be applicable for autosomal and X-linked recessive diseases. This power calculation can most usefully be undertaken after family history data are gathered, but prior to examination and testing of pedigree members to obtain marker information. Of key importance, the power calculation is straightforward to carry out and not too time-consuming; it is practical even on a microcomputer. The result of the power calculation is an objective answer to the question: Will my families be sufficient to demonstrate linkage?

Computer Simulation↗

PubMed2002

Biexponential diffusion attenuation in the rat spinal cord: computer simulations based on anatomic images of axonal architecture.

Water diffusion in neurological tissues is known to possess multicomponent diffusion behavior. The fractions of fast and slow apparent diffusion components have often been attributed to the volume fractions of extracellular space (ECS) and intracellular space (ICS) although diffusion fractions are at variance with the tissue compartment volume ratios. In this article this puzzle was examined with a finite difference diffusion simulation model on the basis of optical images from sectioned rat spinal cord. Here the results show that assignment of fractions obtained from biexponential fits of fast and slow diffusion attenuation to ECS and ICS volume ratios is not correct. Rather, the observed multicomponent diffusion behavior is caused by motional restriction and limited intercompartmental water exchange in that at long diffusion times diffusion attenuation is shown to become monoexponential. Although the measured apparent diffusion fractions also depend on T2 relaxation time of water protons in the various compartments, the sensitivity to T2 is small and thus T2 differences are unlikely to explain the mismatch between apparent diffusion fractions and cellular volume fractions.

Animals↗

PubMed1991

Computer simulations of self-assembled membranes.

Molecular dynamics simulations in three dimensions of particles that self-assemble to form two-dimensional, membrane-like objects are presented. Anisotropic, multibody forces, chosen so as to mimic real interactions between amphiphilic molecules, generate a finite rigidity and compressibility of the assembled membranes, as well as a finite line tension at their free edges. This model and its generalizations can be used to study a large class of phenomena taking place in fluctuating membranes. For instance, both fluid and solid-like phases, separated by a phase transition, are obtained and some of the large-scale properties of these membranes studied. In particular, thermal undulations of quasi-spherical fluid vesicles are analyzed, in a manner similar to recent experiments in lipid systems.

Computer Simulation↗

PubMed1991

Computer simulation of the binding of naphthyridinomycin and cyanocycline A to DNA.

Cyanocycline A was found to have a pKa of 6.6. Protonation of N14 was established by 1H NMR spectroscopy. In strongly acidic solution the oxazolidine ring opened irreversibly. A model was derived for the binding of naphthyridinomycin and cyanocycline A to the hexanucleotide duplex d(ATGCAT)2, by using the molecular mechanics and dynamics modules of AMBER 3.0. It involved protonation on the oxazolidine-ring nitrogen, reduction of the quinone ring to a hydroquinone, formation of an iminium ion with loss of the C7 substituent, noncovalent binding in the minor groove with the hydroquinone ring in the 3'-direction from guanine, and covalent binding to the 2-amino group of this guanine with C7 adopting the R configuration. This model is consistent with the experimental evidence on the DNA binding of these drugs. An alternative binding mode based on opening of the oxazolidine ring and alkylation at C3a also was feasible according to molecular mechanics calculations. The geometry of naphthyridinomycin does not permit interstrand cross-linking involving both C3a and C7, but formation of a cross-link to protein appears possible. When the covalent naphthyridinomycin-d(ATGCAT)2 models were refined in the presence of water and counterions, the models with the most favorable net binding enthalpies were the same as those produced by simulation in vacuum. Qualitative estimates of the relative entropy changes resulting from adduct formation were based on the number of ordered (hydrogen bonded) water molecules released from d(ATGCAT)2 and from the drug. In all cases but one, d(ATGCAT)2 loses five water molecules. It loses six in the C3a covalent model with 5',S geometry. Naphthyridinomycin hydroquinone loses up to two water molecules, depending on the particular adduct. The 3',R model was again favored for the C7 covalent adduct. Among the C3a covalent models, the one with 5',R geometry lost the second most water molecules, but it had the best binding enthalpy.

Alkylation↗

PubMed2005

Electrostatic mechanism of nucleosomal array folding revealed by computer simulation.

Although numerous experiments indicate that the chromatin fiber displays salt-dependent conformations, the associated molecular mechanism remains unclear. Here, we apply an irregular Discrete Surface Charge Optimization (DiSCO) model of the nucleosome with all histone tails incorporated to describe by Monte Carlo simulations salt-dependent rearrangements of a nucleosomal array with 12 nucleosomes. The ensemble of nucleosomal array conformations display salt-dependent condensation in good agreement with hydrodynamic measurements and suggest that the array adopts highly irregular 3D zig-zag conformations at high (physiological) salt concentrations and transitions into the extended "beads-on-a-string" conformation at low salt. Energy analyses indicate that the repulsion among linker DNA leads to this extended form, whereas internucleosome attraction drives the folding at high salt. The balance between these two contributions determines the salt-dependent condensation. Importantly, the internucleosome and linker DNA-nucleosome attractions require histone tails; we find that the H3 tails, in particular, are crucial for stabilizing the moderately folded fiber at physiological monovalent salt.

Computer Simulation↗

PubMed1989

Neuronal loss and neuronal atrophy. Computer simulation in connection with Alzheimer's disease.

A decrease in the number of neuronal profiles in the isocortex of man may be observed on microscopic sections in aging and in degenerative diseases such as Alzheimer's disease. It can be the consequence of a loss of neurons per unit volume or of a reduction of the neuronal volume (i.e. pseudo-loss). This latter possibility has been tested by simulating neuronal atrophy, with sections of various thicknesses. An unfolding algorithm was used for the simulation. The data published in the current literature concerning Alzheimer's disease were treated with the unfolding algorithm. The neocortical pseudo-loss did not exceed a few percentage points, probably much less than the measurement error. New methods of cell counting have been recently proposed to discriminate real from pseudo-loss. They should be used when the risk of dealing with pseudo-loss is high. A chart to assess the percentage of pseudo-loss as a function of perikaryal atrophy is proposed: it relies on the evaluation of the size of the cell relative to the section thickness (relative caliper diameter). This chart may be used to correct cell counts of homogeneous cell populations.

Adult↗

PubMed2000

Model for computer simulation of bone tissue.

The paper deals with the dependence of the torsional moment on the angle of the compact bone torsion in laboratory animals and humans. Based on the data for laboratory animals obtained by measurements, the data on dependence of the torsional moment and the angle of torsion were predicted for humans. The measurements were carried out in four groups of laboratory animals. One was the control group, and the other three groups were treated by various vitamin D3 metabolites. The same measurements were performed also in only one group of humans, due to the impossibility to treat humans with vitamin D3 metabolites. The functional relationship between the angle of torsion and the torsional moment for all the groups of animal bone tissue were determined by measurements, and results were used to predict the reaction of the human compact bone tissue if treated by vitamin D3 metabolites.

Animals↗

PubMed1996

Computer simulation of the binding of amonafide and azonafide to DNA.

Intercalative binding of the antitumor drugs amonafide and azonafide to the oligonucleotide duplex d(GGCCGGCCGG).d(CCGGCCGGCC) was compared using molecular dynamics in vacuum with the AMBER force field. A number of reasonable possible binding conformations were obtained, with the azonafide complexes favored over the amonafide complexes in net binding enthalpy. In comparison with amonafide, the larger chromophore of azonafide permits greater DNA distortion and wider side-chain swings, without falling out of the intercalation site. The best model obtained was used for further dynamics on amonafide and azonafide with solvent and counterions present, and again the azonafide complex had a more favorable enthalpy. Furthermore, the enthalpy change on going from solvent into the intercalation site was less unfavorable for azonafide. These results are consistent with the stronger DNA binding of azonafide compared to amonafide, as observed in relative melting transition temperature increases and tumor inhibition in cell cultures.

Adenine↗

PubMed1995

A method for characterizing transition concertedness from polymer dynamics computer simulations.

A statistical method based on classifying the transitions among a set of dihedral angles within an "energy transfer window" is developed, and used to analyze Brownian (BD) and molecular dynamics (MD) simulations of the acyl chains in a lipid bilayer, and MD of neat hexadecane. It is shown for the BD simulation that when a transition of the dihedral angle in the center of the chain occurs, a transition of a particular next nearest neighbor (or angle 2-apart) will follow concertedly with a probability of approximately 0.10 within a time window of approximately 3 ps. The MD bilayer simulations, which are based on a more flexible model of the hydrocarbon chains, yield corresponding concerted transition probabilities of approximately 0.083 and window sizes of 1-2 ps. An analysis of angles 4-apart yields concerted transition probabilities of 0.03 and 0.04 for the BD and MD bilayer simulations, respectively, and window sizes close to those of the corresponding 2-apart cases. Statistical hypothesis testing very strongly rejects the assertion that these follower transitions are occurring at random. Similar analysis reveals marginal or no evidence of concertedness between 1-apart (nearest neighbor) and between 3-apart dihedral angle transitions. The pattern of concertedness for hexadecane is qualitatively similar to that of the lipid chains, although concertedness is somewhat stronger for the 3-apart transitions and somewhat weaker for those 4-apart. Finally, it is suggested that the diffusion of small solute molecules in membranes is better facilitated by nonconcerted transitions, which are associated with relatively large displacements of the chains, than by concerted transitions, which do little to change the chain shape.

1,2-Dipalmitoylphosphatidylcholine↗

PubMed2002

Computer simulation of the 30-nanometer chromatin fiber.

A new Monte Carlo model for the structure of chromatin is presented here. Based on our previous work on superhelical DNA and polynucleosomes, it reintegrates aspects of the "solenoid" and the "zig-zag" models. The DNA is modeled as a flexible elastic polymer chain, consisting of segments connected by elastic bending, torsional, and stretching springs. The electrostatic interaction between the DNA segments is described by the Debye-Hückel approximation. Nucleosome core particles are represented by oblate ellipsoids; their interaction potential has been parameterized by a comparison with data from liquid crystals of nucleosome solutions. DNA and chromatosomes are linked either at the surface of the chromatosome or through a rigid nucleosome stem. Equilibrium ensembles of 100-nucleosome chains at physiological ionic strength were generated by a Metropolis-Monte Carlo algorithm. For a DNA linked at the nucleosome stem and a nucleosome repeat of 200 bp, the simulated fiber diameter of 32 nm and the mass density of 6.1 nucleosomes per 11 nm fiber length are in excellent agreement with experimental values from the literature. The experimental value of the inclination of DNA and nucleosomes to the fiber axis could also be reproduced. Whereas the linker DNA connects chromatosomes on opposite sides of the fiber, the overall packing of the nucleosomes leads to a helical aspect of the structure. The persistence length of the simulated fibers is 265 nm. For more random fibers where the tilt angles between two nucleosomes are chosen according to a Gaussian distribution along the fiber, the persistence length decreases to 30 nm with increasing width of the distribution, whereas the other observable parameters such as the mass density remain unchanged. Polynucleosomes with repeat lengths of 212 bp also form fibers with the expected experimental properties. Systems with larger repeat length form fibers, but the mass density is significantly lower than the measured value. The theoretical characteristics of a fiber with a repeat length of 192 bp where DNA and nucleosomes are connected at the core particle are in agreement with the experimental values. Systems without a stem and a repeat length of 217 bp do not form fibers.

Biophysical Phenomena↗

PubMed2004

A computer simulation study of water drying at the interface of protein chains.

This study investigated the water drying (cavitation) in the interfacial region of two chains of a dimeric protein by nanosecond molecular dynamics simulations using explicit water representation. Separation-induced cavity of water was directly observed in the region. We evaluated the separation length scale of two chains on which the drying transition occurs, and the average number of water molecules that are expelled from the interfacial region during the transition. The obtained values can be rationalized by Kelvin equation for finite lateral size of confinement [K. Lum and A. Luzar, Phys. Rev. E 56, R6283 (1997)]. Also, we found that the drying transition is accompanied by an exponential reduction in the average hydrogen-bond number per interfacial water molecule. The results of this study may deepen the understanding of how hydrophobic interaction drives the assembly of protein chains.

Amino Acid Sequence↗

PubMed1998

Computer simulation of microscopic cerebral air emboli absorption during cardiac surgery.

Microscopic cerebral arterial air emboli (MCAAE) cause neurologic injury during cardiac surgery. We used a mathematical model of gas absorption to gain a preliminary assessment of what physical or physiologic parameters affect MCAAE absorption in the setting of cardiac surgery with its unique set of normal values. Simulated MCAAE of radii 50 and 200 microns have absorption times of 2 and 32 min, respectively. Predicted absorption times depend dramatically on PaN2. MCAAE are predicted to be absorbed twice as quickly at a PaN2 of 0 vs. 380 mmHg (FiO2 approximately equal to 0.50). Moderate hypothermia (27 degrees C) is predicted to cause only small decreases in absorption time. Changes in cerebral blood flow (for example, as affected by hemoglobin concentration, PaCO2, PaO2, collateral circulation, anesthetics, or cerebral metabolism) probably have only small effects on absorption time. Intravascular perfluorocarbons are predicted to cause small-to-moderate decreases in absorption time. In conclusion, there is probably only one important determinant of MCAAE absorption time during normothermic or moderately hypothermic CPB: arterial nitrogen partial pressure.

Absorption↗

PubMed1994

A computer simulation of the haemodynamic effects of intracranial arteriovenous malformation occlusion.

To study the effect of AVM occlusion on cerebrovascular haemodynamics, a simplified model was simulated consisting of a feeding artery supplying a capillary bed in parallel with a fistula-like malformation, both emptying into a draining vein. An electrical circuit analogue of the physiologic system was developed using lumped proximal and distal pressure dependent resistances, and capacitors representing vascular compliance. Autoregulation was introduced as a pressure varying precapillary arteriolar resistance. Equations derived from the circuit model were simulated using a graphical modeling program. The model successfully simulates phenomena angiographically observed during embolization procedures. Fistula pressure is shown to rapidly fall following proximal AVM occlusion, in contrast to a marked rise seen with distal occlusion, which is associated with biphasic flow into and out of the fistula and the arterial feeder. The model predicts an increase in capillary pressure and capillary flow which, depending on the magnitude of the flow increase and the state of autoregulation, may result either in reversal of ischaemia or hyperperfusion injury. Vascular overload is predicted in the absence of autoregulation. There is, however, little potential for vascular overload when autoregulation is intact. The model represents a first step in the mathematical characterization of the phenomenon of hyperperfusion following AVM occlusion.

Arterial Occlusive Diseases↗

PubMed1998

Computer simulation of heat and mass transfer in tissue during high-intensity long-range laser irradiation.

Three-dimensional transient finite difference numerical model of the biological tissue irradiated by powerful laser beam is developed. It is used to simulate the thermal behavior of tissue assuming that radiation wavelength is chosen to give rise for volumetric heat sources. A three-dimensional seven-flow model is used to calculate radiation propagation. Evaporation and burn-out of tissue resulting in a through hole along the axis of the beam are taken into account. Besides the water boiling and corresponding changes of thermal and optical tissue properties the model takes into account one of the heat steam transfer mechanisms. Estimates are carried out for the effects of diffusion transfer and vaporization of water from the tissue surface. Kinetics of protein denaturation process are calculated by Arrenius equation. The problem is solved numerically using discrete grid technique and adaptive time-step control algorithm.

Body Temperature↗

PubMed1988

Permeability of the blood-retinal barrier in myopia. An analysis employing vitreous fluorophotometry and computer simulation.

Vitreous fluorophotometry was performed in 165 eyes of 93 cases with various degrees of myopia. The age range was 10-39 years. On background of the significant correlation between the refractive diopter value and the length of vitreous cavity, a simulation model for myopia has been established for assessing the permeability of the blood-retinal barrier. Significant negative correlations between the diopter and P-in and the diopter and D-p were found, indicating that by increasing degree of myopia, the functional disorder of the blood-retinal barrier and the liquefaction of the posterior vitreous gel progress. From the comparative study between eyes with slight myopia and eyes with emmetropia, a significant increase in the length of the vitreous cavity and P-in was found in the former, whereas no significant difference was observed in D-p. Therefore, it is suggested that the functional disorder of the blood-retinal barrier in myopia produces the liquefaction of the posterior vitreous gel.

Adolescent↗

PubMed2005

Study of a ligand complexed with Cdk2/Cdk4 by computer simulation.

Cyclin-dependent kinases (Cdks) play important roles in the regulation of the cell cycle. Their inhibitors have entered clinical trials to treat cancer. Very recently, Davis et al. (Nat Struct Biol 9:745-749, 2002) have found a ligand NU6102, which has a high affinity with cyclin-dependent kinase 2 (K(i) = 6 nM) but a low affinity with cyclin-dependent kinase 4 (K(i) = 1,600 nM). To understand the selectivity, we use homology modeling, molecular docking, molecular dynamics and free-energy calculations to analyze the interactions. A rational 3D model of the Cdk4-NU6102 complex is built. Asp86 is a key residue that recognizes NU6102 more effectively with Cdk2 rather than Cdk4. Good binding free energies are obtained. Energetic analysis reveals that van der Waals interaction and nonpolar contributions to solvent are favorable in the formation of complexes and the sulfonamide group of the ligand plays a crucial role for binding selectivity between Cdk2 and Cdk4.

Amino Acid Sequence↗