Asymmetry and free energy transduction in biology

This paper is an extension of our earlier theoretical studies on the relationship between kinetic asymmetry and free-energy transductions in biological systems induced by external fluctuations. In the first part of the paper, the asymmetry conditions necessary for external-noise-induced free-energy transductions to occur are derived for a special cyclic, four-state model in which only one reaction step is perturbed by the fluctuations. The results can be used to explain the earlier findings that asymmetry in rate constants was not required in the uphill transport of ligands induced by externally fluctuating the ligand concentrations. In the second part of the paper, the coupling between two enzyme systems through direct enzyme-enzyme inter-actions is studied. The existence of kinetic asymmetry in both the driving and the driven enzyme systems is found necessary for coupling and free-energy transductions to occur.     

Asymmetric electrotonic coupling between the soma and dendrites alters the bistable firing behaviour of reduced models

The goal of the study was to investigate the influence of asymmetric coupling, between the soma and dendrites, on the nonlinear dynamic behaviour of a two-compartment model. We used a recently published method for generating reduced two-compartment models that retain the asymmetric coupling of anatomically reconstructed motor neurons. The passive input-output relationship of the asymmetrically coupled model was analytically compared to the symmetrically coupled case. Predictions based on the analytic comparison were tested using numerical simulations. The simulations evaluated the nonlinear dynamics of the models as a function of coupling parameters. Analytical results showed that the input resistance at the dendrite of the asymmetric model was directly related to the degree of coupling asymmetry. In contrast, a comparable symmetric model had identical input resistances at both the soma and dendrite regardless of coupling strength. These findings lead to predictions that variations in dendritic excitability, subsequent to changes in input resistance, might change the current threshold and onset timing of the plateau potential generated in the dendrite. Since the plateau potential underlies bistable firing, these results further predicted that asymmetric coupling might alter nonlinear (i.e. bistable) firing patterns. The numerical simulations supported analytical predictions, showing that the fully bistable firing pattern of the asymmetric model depended on the degree of coupling asymmetry and its correlated dendritic excitability. The physiological property of asymmetric coupling plays an important role in generating and stabilizing the bistability of motor neurons by interacting with the excitability of dendritic branches.     

Modulating L-type calcium current affects discontinuous cardiac action potential conduction.

We have used pairs of cardiac cells (i.e., one real guinea pig ventricular cell and a real-time simulation of a numerical model of a guinea pig ventricular cell) to evaluate the effects on action potential conduction of a variable coupling conductance in combination with agents that either increase or decrease the magnitude of the L-type calcium current. For the cell pairs studied, we applied a direct repetitive stimulation to the real cell, making it the "leader" cell of the cell pair. We have demonstrated that significant delays in action potential conduction for a cell pair can occur either with a decreased value of coupling conductance or with an asymmetry in size such that the follower cell is larger than the leader cell. In both conditions we have shown that isoproterenol, applied to the real cell at very low concentrations, can reversibly decrease the critical coupling conductance (below which action potential conduction fails) for a cell pair with fixed cell sizes, or, for a fixed value of coupling conductance, increase the maximum allowable asymmetry in cell size for successful conduction. For either of these effects, we were able to show that treatment of the real cell with BayK 8644, which more specifically increases the magnitude of the L-type calcium current, was able to mimic the actions of isoproterenol. Treatment of the leader cell of the cell pair (the real cell) with nifedipine, which selectively lowers the magnitude of the L-type calcium current, had effects opposite those of isoproterenol or BayK 8644. The actions of nifedipine, isoproterenol, and BayK 8644 are all limited to conditions in which the conduction delay is on the order of 5 ms or more, whether this delay is caused by limited coupling conductance or by asymmetry in size of the cells. This limitation is consistent with the time course of the L-type calcium current and suggests that the effects of calcium channel blockers or beta-adrenergic blocking drugs, in addition to being selective for regions of the heart that depend on the L-type calcium current for the upstroke of the action potential, would also be somewhat selective for regions of the heart that have discontinuous conduction, either normally or because of some pathological condition.     

Asymmetrical habitat coupling of an aquatic predator—The importance of individual specialization

Predators should stabilize food webs because they can move between spatially separate habitats. However, predators adapted to forage on local resources may have a reduced ability to couple habitats. Here, we show clear asymmetry in the ability to couple habitats by Eurasian perch—a common polymorphic predator in European lakes. We sampled perch from two spatially separate habitats—pelagic and littoral zones—in Lake Erken, Sweden. Littoral perch showed stronger individual specialization, but they also used resources from the pelagic zone, indicating their ability to couple habitats. In contrast, pelagic perch showed weaker individual specialization but near complete reliance on pelagic resources, indicating their preference to one habitat. This asymmetry in the habitat coupling ability of perch challenges the expectation that, in general, predators should stabilize spatially separated food webs. Our results suggest that habitat coupling might be constrained by morphological adaptations, which in this case were not related to genetic differentiation but were more likely related to differences in individual specialization.     

Asymmetric GUVs Prepared by MβCD-Mediated Lipid Exchange: An FCS Study

We report a simple method to obtain stable asymmetric giant unilamellar vesicles (GUVs). Fluorescence correlation spectroscopy was used to quantitatively characterize vesicle properties. After brain sphingomyelin (bSM) was exchanged into dioleoylphosphatidylcholine (DOPC) GUVs, lateral diffusion in the bSM-containing outer leaflet decreased, whereas that in the DOPC-containing inner leaflet was largely unchanged, confirming asymmetry and a lack of coupling between the physical states of the inner and outer leaflets. In contrast, after bSM was exchanged into brain phosphatidylcholine vesicles, lateral diffusion decreased in both leaflets. Thus, asymmetric GUVs should be useful for investigating the molecular mechanisms behind interleaflet coupling.     

On the function of cell systems in area 18. Part II

In addition to the asymmetry of the spatial coupling and of the specific temporal combination of excitation and inhibition, the non-linearity is very pronounced in area 18. Taking the sequence of a linear operation and a stationary nonlinear characteristic as a model, the experimental findings can be systematized and a cell classification specified which departs from the customary ones. The hypercomplex cell system probably originates in recurrent inhibition and leads to differentiation of the patterns along their contour line. Problems of cell classification and of the type of parallelism in the visual cortex are discussed.This research was supported by DFG Grants Se 251/14 and Se 251/16     

Effect of Crown Asymmetry on Size-Structure Dynamics of Plant Populations

The effect of crown asymmetry on the size–structure dynamicsof populations was evaluated using a spatial competition modelincorporating crown asymmetry. Computer simulations were carriedout with various combinations of density levels, spatial patterns,and degrees of asymmetry in competition to assess how they modifythe effect of crown asymmetry on size–structure dynamics. In the model, crown asymmetry is expressed by the crown-vector,or the vector linking the stem base and the centre of the projectedarea of the crown on the horizontal plane. Crown-vectors areassumed to develop in the manner by which crowns repel eachother. As crown-vectors develop, the positions of the crown-centresmove. Competition between individuals is expressed by a neighbourhoodmodel, in which individual growth is determined by the distancefrom, and size of, the neighbours' crown-centres. Generally, populations of individuals which developed asymmetriccrowns had larger survivorship, larger mean size, smaller coefficientsof variation and skewness, and a more regular spatial patternthan populations of individuals which developed symmetric crowns.The effect of crown symmetry is generally stronger in populationswith high density and a clumped spatial pattern. The effectof mortality caused by one-sided competition on size-structuredynamics was similar to that of crown asymmetry; mortality increasedmean size, reduced size hierarchy, and made the spatial patternmore regular. Because mortality was heavier in populations withoutcrown asymmetry, its effect on size-structure dynamics cancelledout, or overwhelmed, the effect of crown asymmetry in latergrowth stages. If crown asymmetry is associated with a reductionin growth, the effect of crown asymmetry is reduced. Nevertheless,the resultant population structure is different from that ofpopulations without crown asymmetry. Competition; crown asymmetry; morphological plasticity; neighbourhood interference model; size-structure dynamics     

A structural analysis of asymmetry required for catalytic activity of an ABC-ATPase domain dimer

The ATP-binding cassette (ABC)-transporter haemolysin (Hly)B, a central element of a Type I secretion machinery, acts in concert with two additional proteins in Escherichia coli to translocate the toxin HlyA directly from the cytoplasm to the exterior. The basic set of crystal structures necessary to describe the catalytic cycle of the isolated HlyB-NBD (nucleotide-binding domain) has now been completed. This allowed a detailed analysis with respect to hinge regions, functionally important key residues and potential energy storage devices that revealed many novel features. These include a structural asymmetry within the ATP dimer that was significantly enhanced in the presence of Mg2+, indicating a possible functional asymmetry in the form of one open and one closed phosphate exit tunnel. Guided by the structural analysis, we identified two amino acids, closing one tunnel by an apparent salt bridge. Mutation of these residues abolished ATP-dependent cooperativity of the NBDs. The implications of these new findings for the coupling of ATP binding and hydrolysis to functional activity are discussed.     

Neural networks for computing eigenvalues and eigenvectors

We consider two electrically coupled oscillators described by modified Fitzhugh-Nagumo equations. We study the relative influence of the individual cellular characteristics and the electrical coupling on the behavior of the coupled system. We show that, for similar oscillators, the load effect of the slow oscillator increases with the coupling strength. We prove that an asymmetry between the uncoupled bursters can accelerate the system with respect to the free cells, this effect depending on the characteristics of the coupling.On leave from Centre de Physique Théoruique (UPR A0014 CNRS), Palaiseau, France     

On the function of cell systems in area 18. Part I

Proceeding from previous studies on cells in area 18, neurophysiological experiments were carried out using combinations of deterministic and statistical stimuli. The evaluation of the results on the space, time and amplitude characteristics of the cells show that for nearly all cells in this area, pattern distorition and shift due to motion are eliminated by spatial asymmetry of the coupling and specific combinations of on-off systems. So, the extraction of features despite pattern movement is possible in area 18. The features are extracted in the low spatial frequency range.This research was supported by DFG Grants Se 251/14 and Se 251/16     

Diversification and co-option of RAD-like genes in the evolution of floral asymmetry

To understand how changes in gene regulatory networks lead to novel morphologies, we have analysed the evolution of a key target gene, RAD, controlling floral asymmetry. In Antirrhinum, flower asymmetry depends on activation of RAD in dorsal regions of the floral meristem by the upstream regulators CYC and DICH. We show that Arabidopsis, a species with radially symmetric flowers, contains six RAD-like genes, reflecting at least three duplications since the divergence of Antirrhinum and Arabidopsis. Unlike the situation in Antirrhinum, none of the Arabidopsis RAD-like genes are activated in dorsal regions of the flower meristem. Rather, the RAD-like genes are expressed in distinctive domains along radial or ab-adaxial axes, consistent with a range of developmental roles. Introduction of a RAD genomic clone from Antirrhinum into Arabidopsis leads to a novel expression pattern that is distinct from the expression pattern of RAD in Antirrhinum and from the endogenous RAD-like genes of Arabidopsis. Nevertheless, RAD is able to influence developmental targets in Arabidopsis, as ectopic expression of RAD has developmental effects in this species. Taken together, our results suggest that duplication and divergence of RAD-like genes has involved a range of cis- and trans-regulatory changes. It is possible that such changes led to the coupling of RAD to CYC regulation in the Antirrhinum lineage and hence the co-option of RAD had a role in the generation of flower dorsoventral asymmetry.     

Heme geometry in the 10 K photoproduct from sperm whale carbonmonoxymyoglobin

We have measured the Soret band of the photoproduct obtained by complete photolysis of sperm whale carbonmonoxymyoglobin at 10 K. The experimental spectrum has been modeled with an analytical expression that takes into account the homogeneous bandwidth, the coupling of the electronic transition with both high and low frequency vibrational modes, and the effects of static conformational heterogeneity. The comparison with deoxymyoglobin at low temperature reveals three main differences. In the photoproduct, the Soret band is shifted to red. The band is less asymmetric, and an enhanced coupling to the heme vibrational mode at 674 cm⁻¹ is observed. These differences reflect incomplete relaxation of the active site after ligand dissociation. The smaller band asymmetry of the photoproduct can be explained by a smaller displacement of the iron atom from the mean porphyrin plane, in quantitative agreement with the X-ray structure analysis. The enhanced vibrational coupling is attributed to a subtle heme distortion from the planar geometry that is barely detectable in the X-ray structure.     

Origin of Twist-Bend Coupling in Actin Filaments

Actin filaments are semiflexible polymers that display large-scale conformational twisting and bending motions. Modulation of filament bending and twisting dynamics has been linked to regulatory actin-binding protein function, filament assembly and fragmentation, and overall cell motility. The relationship between actin filament bending and twisting dynamics has not been evaluated. The numerical and analytical experiments presented here reveal that actin filaments have a strong intrinsic twist-bend coupling that obligates the reciprocal interconversion of bending energy and twisting stress. We developed a mesoscopic model of actin filaments that captures key documented features, including the subunit dimensions, interaction energies, helicity, and geometrical constraints coming from the double-stranded structure. The filament bending and torsional rigidities predicted by the model are comparable to experimental values, demonstrating the capacity of the model to assess the mechanical properties of actin filaments, including the coupling between twisting and bending motions. The predicted actin filament twist-bend coupling is strong, with a persistence length of 0.15-0.4 μm depending on the actin-bound nucleotide. Twist-bend coupling is an emergent property that introduces local asymmetry to actin filaments and contributes to their overall elasticity. Up to 60% of the filament subunit elastic free energy originates from twist-bend coupling, with the largest contributions resulting under relatively small deformations. A comparison of filaments with different architectures indicates that twist-bend coupling in actin filaments originates from their double protofilament and helical structure.     

The kinetics of phase separation in asymmetric membranes

Phase separation in a model asymmetric membrane is studied using Monte Carlo techniques. The membrane comprises two species of particles, which mimic different lipids in lipid bilayers and separately possess either zero or non-zero spontaneous curvatures. We study the influence of phase separation on membrane shape and the influence of the coupling of composition and height dynamics on phase separation and domain growth, via both the degree of shape asymmetry and relative kinetic coefficients for height relaxation.     

Role of the hypophysis in fixing postural asymmetry at the segmental level in hemisection of the spinal cord

The role of the pituitary in the mechanisms of posttraumatic reorganizations of the segmental apparatus was studied. Hypophysectomized rats failed to demonstrate postural asymmetry after spinal cord hemisection. The lack of asymmetry is connected with a considerable decrease in postural asymmetry factor activity in the cerebrospinal fluid and cerebral tissue. It was established that pituitary tissue is characterized by the maximal level of postural asymmetry factor activity after hemisection.     

Ganglioside GM1 forces the redistribution of cholesterol in a biomimetic membrane

Neutron reflectivity has been applied to investigate different mixed asymmetric lipid systems, in the form of single "supported+floating" bilayers, made of phospholipids, cholesterol and GM1 ganglioside (Neu5Acα2-3(Galβ1-3GalNAcβ1-4)Galβ1-4Glcβ1Cer)) in bio-similar mole ratios. Bilayer preparation was carried out layer-by-layer with the Langmuir-Blodgett Langmuir-Schaefer techniques, allowing for compositional asymmetry in the system buildup. It is the first time that such a complex model membrane system is reported. Two important conclusions are drawn. First, it is experimentally shown that the presence of GM1 enforces an asymmetry in cholesterol distribution, opposite to what happens for a GM1-free membrane that, submitted to a similar procedure, results in a full symmetrization of cholesterol distribution. We underline that natural cholesterol has been used. Second, and most interesting, our results suggest that a preferential asymmetric distribution of GM1 and cholesterol is attained in a model membrane with biomimetic composition, revealing that a true coupling between the two molecular species occurs.     

Iron-histidine resonance raman band of deoxyheme proteins: effects of anharmonic coupling and glass-liquid phase transition

Weak anharmonic coupling of two soft molecular vibrations is shown to cause pronounced temperature dependence of the corresponding resonance Raman bands. The developed theory is used to interpret the temperature dependence of the iron-histidine band of deoxyheme proteins and model compounds. It is shown that anharmonic coupling of the iron-histidine and heme doming vibrations must cause pronounced broadening of the band, its asymmetry, and shift of its maximum to the red upon heating. It also can lead to a structured shape of this band at room temperature. Proper consideration of the anharmonic coupling allows simulation of the temperature dependence of the iron-histidine band shape of horse heart myoglobin in the temperature interval of 10-300 K, using the minimum number of necessary parameters. Analysis of this temperature dependence clearly shows that the iron-histidine band of deoxyheme proteins is sensitive to the glass-liquid phase transition in the protein hydration shell, which takes place at 160-190 K.     

Inbreeding reduces power-law scaling in the distribution of fluctuating asymmetry: an explanation of the basis of developmental instability

The study of fluctuating asymmetry has been controversial because of conflicting results found in much of the primary literature. It has been suggested that the source of this conflict is the fact that the basis of fluctuating asymmetry is poorly understood and that, as a consequence, methodology of fluctuating asymmetry studies may be flawed. A new model for the phenomenological basis of fluctuating asymmetry, that variation in fluctuating asymmetry is in large part due to the random exponential growth of cell populations (geometric Brownian motion) that are terminated randomly around a genetically programmed development time, is presented here. If termination of development has a genetic component, then scaling effects and kurtosis in the distribution of fluctuating asymmetry should increase with genetic redundancy of the population. This model prediction was tested by comparing the distribution of multivariate size and shape fluctuating asymmetry in large samples collected from both wild populations and four moderately inbred lines of Drosophila simulans. It was found that while wild populations were best described by a lognormal distribution with power-law scaled tails, the inbred lines derived from the wild stock were dramatically normalized (half-normal) in three of four cases. As predicted, the scaling exponent of the upper tail of the distribution of fluctuating asymmetry increased with inbreeding while the kurtosis and mean fluctuating asymmetry decreased with inbreeding. The model suggests an additional explanation of leptokurtosis in fluctuating asymmetry. Kurtosis and scaling of the statistical distribution of fluctuating asymmetry in a population is related directly to genetic differences between individuals and these differences affect their ability to buffer the process of development against random perturbations.     

Assessing spatial coupling in complex population dynamics using mutual prediction and continuity statistics

A number of important questions in ecology involve the possibility of interactions or "coupling" among potential components of ecological systems. The basic question of whether two components are coupled (exhibit dynamical interdependence) is relevant to investigations of movement of animals over space, population regulation, food webs and trophic interactions, and is also useful in the design of monitoring programs. For example, in spatially extended systems, coupling among populations in different locations implies the existence of redundant information in the system and the possibility of exploiting this redundancy in the development of spatial sampling designs. One approach to the identification of coupling involves study of the purported mechanisms linking system components. Another approach is based on time series of two potential components of the same system and, in previous ecological work, has relied on linear cross-correlation analysis. Here we present two different attractor-based approaches, continuity and mutual prediction, for determining the degree to which two population time series (e.g., at different spatial locations) are coupled. Both approaches are demonstrated on a one-dimensional predator-prey model system exhibiting complex dynamics. Of particular interest is the spatial asymmetry introduced into the model as linearly declining resource for the prey over the domain of the spatial coordinate. Results from these approaches are then compared to the more standard cross-correlation analysis. In contrast to cross-correlation, both continuity and mutual prediction are clearly able to discern the asymmetry in the flow of information through this system.