Theoretical mimicry of biomembranes

The study of membrane proteins requires a proper consideration of the specific environment provided by the biomembrane. The compositional complexity of this environment poses great challenges to all experimental and theoretical approaches. In this article a rather simple theoretical concept is discussed for its ability to mimic the biomembrane. The biomembrane is approximated by three mimicry solvents forming individual continuum layers of characteristic physical properties. Several specific structural problems are studied with a focus on the biological significance of such an approach. Our results support the general perception that the biomembrane is crucial for correct positioning and embedding of its constituents. The described model provides a semi-quantitative tool of potential interest to many problems in structural membrane biology.     

Recent advances in Membrane Biochemistry

This Biochemical Society Annual Symposium on Recent Advances in Membrane Biochemistry was organized to bring together experts from across the spectrum of biomembrane disciplines from the biological to the biophysical/structural, with the intention of promoting interactions and collaborations across the field. We were keen that the potential for improving human health that stems from a deeper understanding of membrane structure/function should be acknowledged, especially in the light of the increasing numbers of membrane protein structures that continue to be made available to the biomembrane community. This foreword provides an idea of what was communicated in the various sessions and, we hope, gives an impression of the excitement generated by the speakers and delegates at this over-subscribed Symposium.     

Lipid reorganization in biological membranes. A study by fourier transform infrared difference spectroscopy

The first application of infrared difference spectroscopy to the study of a natural biological membrane is described. Perdeuterated palmitic acid was incorporated biosynthetically into the lipids of the plasma membrane of Acholeplasma laidlawii and the temperature-induced structural rearrangement of the endogenous lipids monitored via their C²H vibrational modes. Changes in infrared parameters were studied between 0 and 50°C and contrasted with those occurring in the model membrane system of $\text{1,2-}\text{diperdeuteropalmitoyl}\text{-sn-}\text{glycero-3-phosphocholine}$. The phase transition of the biomembrane occurs over a 20°C range with the temperature of the maximum rate of change of absorbance coinciding with that of the sharp phase transition of the model membrane.     

Das Hämoglobinmolekül in kybernetischer und thermodynamischer Beziehung

Summary The biological macromolecule hemoglobin (Hb) represents a reversibly functioning molecular machine. The Hb molecule is engaged in inner or structural work, which is cyclic in nature and is regulated through an exchange with the external milieu, of warmth and matter. The endothermic process of deoxygenation requires an external milieu that gives off warmth and that absorbs oxygen; the exothermic process of oxygenation, on the other hand, requires an external milieu that absorbs warmth and gives up oxygen. The Hb molecule exists in two extreme states: in a signal state for oxygenation and in a target state for deoxygenation. The transition from the signal to the target state occurs via the information process that is coupled to the structural work of the Hb molecule, whereby the absorbed warmth is converted via the structural work, without loss of energy, into the structural energy of the Hb molecule.     

Dynamical Modeling of the Cell Cycle and Cell Fate Emergence in Caulobacter crescentus

The division of Caulobacter crescentus, a model organism for studying cell cycle and differentiation in bacteria, generates two cell types: swarmer and stalked. To complete its cycle, C. crescentus must first differentiate from the swarmer to the stalked phenotype. An important regulator involved in this process is CtrA, which operates in a gene regulatory network and coordinates many of the interactions associated to the generation of cellular asymmetry. Gaining insight into how such a differentiation phenomenon arises and how network components interact to bring about cellular behavior and function demands mathematical models and simulations. In this work, we present a dynamical model based on a generalization of the Boolean abstraction of gene expression for a minimal network controlling the cell cycle and asymmetric cell division in C. crescentus. This network was constructed from data obtained from an exhaustive search in the literature. The results of the simulations based on our model show a cyclic attractor whose configurations can be made to correspond with the current knowledge of the activity of the regulators participating in the gene network during the cell cycle. Additionally, we found two point attractors that can be interpreted in terms of the network configurations directing the two cell types. The entire network is shown to be operating close to the critical regime, which means that it is robust enough to perturbations on dynamics of the network, but adaptable to environmental changes.     

生物膜研究在生物物理研究所的兴起与发展

生物膜研究是现代生物学研究的前沿方向之一,本文对文革结束以后生物膜研究在中国科学院生物物理研究所(下称生物物理所)的兴起与发展进行了系统回顾.文革结束后,中国科学院领导了解到国外生物膜研究迅速发展的情况,迅即派遣以生物物理所杨福愉为组长,包括生物化学研究所、动物研究所、植物研究所、上海实验生物研究所等六人的代表团前往联邦德国进行考察.考察结束后院领导根据多学科交叉对生物膜研究的重要作用,组织了生物物理所、植物所、中国医学科学院、北京医科大学等单位联合申报国家自然科学基金委员会重大项目"膜脂-膜蛋白的相互作用及其在医学和农业上的应用",并获得立项.与此同时,院领导建议由中国生物物理学会、中国生化学会和中国细胞生物学会共同组织生物膜学术讨论会.首次会议于1979年3月在北京友谊宾馆举行,以后每3年召开1次,从未中断,有力地促进了生物膜研究的交流与发展.2003年举行的第200届香山会议专门组织讨论21世纪生物膜研究在中国的布局,进一步推动了生物膜研究的发展.本文还重点阐述了中国科学院生物物理研究所在生物膜研究方面所取得的代表性成果:a.金属离子通过膜脂-膜蛋白相互作用调控生物膜能量转换、物质运输及信号转导的分子机制;b.提出"克山病是一种心肌线粒体病"的重要观点;c.发现溶酶体内含有为量甚微、一般认为是消化酶的胰凝乳蛋白酶,并阐明了它通过溶酶体膜外泄后参与细胞凋亡的作用机制;d.确定了通过调控线粒体动态变化而干预肿瘤细胞迁移侵袭的新靶标.最后,特别值得一提的是,2004年,常文瑞与植物研究所匡廷云等在《自然》(Nature)发表了《菠菜中主要捕光色素复合体2.72魡分辨率的晶体结构分析》的研究论文,2005年饶子和与徐建兴等在《细胞》(Cell)发表了《猪心线粒体呼吸链复合体Ⅱ的晶体结构》的研究论文,充分标志着我国生物膜研究已在国际上占据一席之地.2004年,徐涛研究员因其在囊泡转运方面的丰厚学术积淀,作为首席科学家组织一批生物膜专家承担了国内首个生物膜973项目,这标志着国内生物膜研究开始进入一个新的发展时期.     

Fission of biological membranes: interplay between dynamin and lipids

Membrane budding and fission are the key stages of ubiquitous processes of formation of intracellular transport vesicles. We present a theoretical consideration of one of the most important types of fission machinery, which is mediated by GTPase dynamin and controlled by lipid composition of the membrane. We suggest a mechanism for collapse of a membrane neck driven by interplay between the dynamin collar and the bending elastic energy of the neck membrane. The collar plays a role of a rigid external skeleton, which imposes mechanical constraints on the neck. We show that in certain conditions the membrane of the neck loses its stability and collapses. Collapse can result from: (i) shifting of the spontaneous curvature of the neck membrane towards negative values, (ii) stretching of the dynamin collar, (iii) tightening of the dynamin collar. The three factors can act separately or concertedly. The suggested model accounts for the major experimental knowledge on membrane fission mediated by dynamin. It includes the elements of all previous models of dynamin action based on different sets of experimental results [Sever et al., Traffic 2000; 1: 385-392]. It reconciles, at least partially, the apparent contradictions between the existing alternative views on biomembrane fission machinery.     

Dynamics of prostate cancer stem cells with diffusion and organism response

We develop a systems based model for prostate cancer, as a sub-system of the organism. We accomplish this in two stages. We first start with a general ODE that includes organism response terms. Then, to account for normally observed spatial diffusion of cell populations, the ODE is extended to a PDE that includes spatial terms. Numerical solutions of the full PDE are provided, and are indicative of traveling wave fronts. This motivates the use of a well known transformation to derive a canonically related (non-linear) system of ODEs for traveling wave solutions. For biological feasibility, we show that the non-negative cone for the traveling wave system is time invariant. We also prove that the traveling waves have a unique global attractor. Biologically, the global attractor would be the limit for the avascular tumor growth. We conclude with comments on clinical implications of the model.     

Co-evolution of cytochrome c 6 and plastocyanin, mobile proteins transferring electrons from cytochrome b 6f to photosystem I

 Cytochrome c ₆ and plastocyanin are soluble metalloproteins that act as mobile carriers transferring electrons between the two membrane-embedded photosynthetic complexes cytochrome b ₆ f and photosystem I (PSI). First, an account of recent data on structural and functional features of these two membrane complexes is presented. Afterwards, attention is focused on the mobile heme and copper proteins – and, in particular, on the structural factors that allow recognition and confer molecular specificity and control the rates of electron transfer from and to the membrane complexes. The interesting question of why plastocyanin has been chosen over the ancient heme protein is discussed to place emphasis on the evolutionary aspects. In fact, cytochrome c ₆ and plastocyanin are presented herein as an excellent case study of biological evolution, which is not only convergent (two different structures but the same physiological function), but also parallel (two proteins adapting themselves to vary accordingly to each other within the same organism). Received: 4 July 1996 / Accepted: 16 September 1996     

Comparative studies on Ureide Permeases in Arabidopsis thaliana and analysis of two alternative splice variants of AtUPS5

The recovery of free purine and pyrimidine bases and their degradation products represent alternative pathways in plant cells either to synthesize nucleotides (salvage pathways) by low energy consumption or to reuse organic nitrogen. Such recycling of metabolites often requires their uptake into the cell by specialized transport systems residing in the plasma membrane. In plants, it has been suggested that several protein families are involved in this process, but only a few transporters have so far been characterized. In this work, gene expression, substrate specificities, and transport mechanisms of members of the Ureide Permease family in Arabidopsis (AtUPS) were analyzed and compared. Promoter-GUS studies indicated that the members of the family have distinct and partially overlapping expression patterns with regard to developmental stages or tissue specific localization. In addition, two alternative splice variants of AtUPS5, a novel member of the transporter family, were identified and investigated. The abundance of both alternative mRNAs varied in different organs, while the relative amounts were comparable. AtUPS5l (longer isoform) shares similar structural prediction with AtUPS1 and AtUPS2. In contrast, AtUPS5s (shorter isoform) lacks two transmembrane domains as structural consequence of the additional splice event. When expressed in yeast, AtUPS5l mediates cellular import of cyclic purine degradation products and pyrimidines similarly to AtUPS1 and AtUPS2, but differences in transport efficiencies were observed. AtUPS5s, however, could not be shown to mediate uptake of these compounds into yeast cells and might therefore be defective or have a different function.     

Life Stages: Interactions and Spatial Patterns

In many stage-structured species, different life stages often occupy separate spatial niches in a heterogeneous environment. Life stages of the giant flour beetle Tribolium brevicornis (Leconte), in particular adults and pupae, occupy different locations in a homogeneous habitat. This unique spatial pattern does not occur in the well-studied stored grain pests T. castaneum (Herbst) and T. confusum (Duval). We propose density dependent dispersal as a causal mechanism for this spatial pattern. We model and explore the spatial dynamics of T. brevicornis with a set of four density dependent integrodifference and difference equations. The spatial model exhibits multiple attractors: a spatially uniform attractor and a patchy attractor with pupae and adults spatially separated. The model attractors are consistent with experimental observations.     

Stable oscillations in mathematical models of biological control systems

Summary Oscillations in a class of piecewise linear (PL) equations which have been proposed to model biological control systems are considered. The flows in phase space determined by the PL equations can be classified by a directed graph, called a state transition diagram, on anN-cube. Each vertex of theN-cube corresponds to an orthant in phase space and each edge corresponds to an open boundary between neighboring orthants. If the state transition diagram contains a certain configuration called a cyclic attractor, then we prove that for the associated PL equation, all trajectories in the regions of phase space corresponding to the cyclic attractor either (i) approach a unique stable limit cycle attractor, or (ii) approach the origin, in the limitt→∞. An algebraic criterion is given to distinguish the two cases. Equations which can be used to model feedback inhibition are introduced to illustrate the techniques.     

Unravelling the molecular basis of the selectivity of the HIV-1 fusion inhibitor sifuvirtide towards phosphatidylcholine-rich rigid membranes

Sifuvirtide, a 36 amino acid negatively charged peptide, is a novel HIV-1 fusion inhibitor with improved antiretroviral activity. In this work we evaluated the physical chemistry foundation of the interaction of sifuvirtide with biomembrane model systems. Since this peptide has aromatic residues, fluorescence spectroscopy techniques were mostly used. The interaction was assessed by partition and quenching experiments. Results showed no significant interaction with large unilamellar vesicles composed by sphingomyelin and ceramide. In contrast, sifuvirtide presented selectivity towards vesicles composed by phosphatidylcholines (PC) in the gel phase, in opposition to fluid phase PC vesicles. The interaction of this peptide with gel phase PC membranes (K_p = 1.2 × 10²) is dependent on the ionic strength, which indicates the mediation of electrostatic interactions at an interfacial level. The effects of sifuvirtide on the lipid membranes' structural properties were further evaluated using dipole-potential membrane probes, zeta-potential, dynamic light scattering and atomic force microscopy measurements. The results show that sifuvirtide does not cause a noticeable effect on lipid bilayer structure, except for membranes composed by cationic phospholipids. Altogether, we can conclude that sifuvirtide presents a specific affinity towards rigid PC membranes, and the interaction is mediated by electrostatic factors, not affecting the membrane architecture.     

Biomembrane elastic response to intercalation of amphiphiles

A model of the elastic behavior of a biomembrane in response to intercalation of amphiphiles into the bilayer is developed. This model takes into account the bilayer couple hypothesis (Sheetz and Singer 1974), and assumes that incorporation of amphiphiles into one layer of the membane exerts mechanical work on the elastic biomembrane. The model accounts for an apparent experimental discordance noted by several authors: the variation in area observed upon incorporating amphiphiles is smaller by a factor of about 2 than the variation expected using previous models. Offprint requests to: E. Farge     

Effects of small nonpolar molecules on membrane compressibility and permeability: A theoretical study of the effects of anesthetic gases

We explore from a theoretical perspective the effects of small nonpolar molecules, such as anesthetic gases, on membrane compressibility and permeability. As a model system we expand a previously proposed generalization of Nagle's model for biomembrane phase transitions. In this model anesthetic gases alter membrane compressibility, causing profound changes in membrane permeability. Anesthetics either increase or decrease membrane permeability, depending on whether the membrane lipid is originally in the solid or melted state, or in a two-phase region. These changes are reversed by high pressure, in agreement with experimental results. Anesthetic-induced changes in compressibility are predicted to inhibit fusion of phospholipid vesicles to each other and to planar bilayers, and thus might be expected to inhibit the fusion of presynaptic vesicles with the presynaptic nerve membrane. This work provides a detailed molecular theory for many of the effects of anesthetic gases on both synapse and axon, and provides a coherent framework for understanding diverse experimental results.     

The lethal plant defense paradox remains: inducible host-plant aristolochic acids and the growth and defense of the pipevine swallowtail

Toxic plants with sequestering specialists are presented with a problem because plant derived toxins protect herbivores against natural enemies. It has been suggested that early induction of toxins and later relaxation of these defenses may help the plant resolve this problem because neonate caterpillars incur the physiological cost of dealing with toxins in early life, but are denied toxins when they are able to sequester them efficiently. In California, the pipevine swallowtail, Battus philenor L. (Lepidoptera: Papilionidae), feed exclusively on Aristolochia californica Torrey (Aristolochiaceae), an endemic vine that contains toxic alkaloids called aristolochic acids that caterpillars sequester to provide chemical defense in immature and adult stages. In a field experiment, the concentration of aristolochic acids doubled in the plant following leaf damage and returned to constitutive levels after six days. Neonate pipevine swallowtail caterpillars showed no aversion to high levels of aristolochic acid in a preference test. Caterpillars reared on leaves with supplemented aristolochic acid showed no physiological cost or increased mortality compared to caterpillars reared on un-supplemented leaves. Searching efficiency and capture rate of lacewing larvae (Chrysoperla), a common predator of first instar caterpillars, was compromised significantly after feeding on caterpillars reared on leaves with supplemented concentrations of aristolochic acid compared to caterpillars feeding on control plants. Additionally, mortality of lacewings increased when they were provided with a diet of B. philenor caterpillars reared on supplemented leaves compared to caterpillars reared on control leaves. Thus, the induction of aristolochic acids in the plant following leaf damage does not resolve the problem confronted by the plant and may confer benefits to this sequestering specialist.     

Antioxidant effect of capsaicin on lipid peroxidation in homogeneous solution,micelle dispersions and liposomal membranes

Abstract

The antioxidant activity of capsaicin (CAP) was measured in the oxidation of methyl linoleate (ML) in homogeneous solution, of ML micelles in aqueous dispersions and also of soybean phosphatidylcholine liposomal membrane, and was compared to that of -tocopherol (-TOH) which is one of the most important antioxidants in vivo. The reactivity of CAP toward galvinoxyl (a model phenoxyl radical) in acetonitrile solution was found to be much smaller than that of -TOH, suggesting that the radical scavenging activity of CAP is much weaker than that of -TOH. In fact, in homogeneous acetonitrile solution where the antioxidant activity is determined primarily by the chemical activity of the antioxidant toward peroxyl radicals, CAP inhibited the oxidation of ML much less efficiently than -TOH and a clear induction period was not observed. The antioxidant activity of CAP was found to be about 60 times smaller than that of -TOH in homogeneous solution. However, in micelle oxidation, the difference in antioxidant activity of the two antioxidants was much smaller than in homogeneous solution. Furthermore, in the membrane, CAP inhibited the oxidation almost as effectively as -TOH. These results suggest that CAP can act as an antioxidant in the biomembrane.     

Neuronal Mechanisms Encoding Global-to-Fine Information in Inferior-Temporal Cortex

Sugase et al. found that global information is represented at the initial transient firing of a single face-responsive neuron in inferior-temporal (IT) cortex, and that finer information is represented at the subsequent sustained firing. A feed-forward model and an attractor network are conceivable models to reproduce this dynamics. The attractor network, specifically an associative memory model, is employed to elucidate the neuronal mechanisms producing the dynamics. The results obtained by computer simulations show that a state of neuronal population initially approaches to a mean state of similar memory patterns, and that it finally converges to a memory pattern. This dynamics qualitatively coincides with that of face-responsive neurons. The dynamics of a single neuron in the model also coincides with that of a single face-responsive neuron. Furthermore, we propose two physiological experiments and predict the results from our model. Both predicted results are not explainable by the feed-forward model. Therefore, if the results obtained by actual physiological experiments coincide with our predicted results, the attractor network might be the neuronal mechanisms producing the dynamics of face-responsive neurons.     

Perturbation approximation of solutions of a nonlinear inverse problem arising in olfaction experimentation

In this paper, a mathematical model of the diffusion of cAMP into olfactory cilia and the resulting electrical activity is presented. The model, which consists of two nonlinear differential equations, is studied using perturbation techniques. The unknowns in the problem are the concentration of cAMP, the membrane potential, and the quantity of most interest in this work: the distribution of CNG channels along the length of a cilium. Experimental measurements of the total current during this diffusion process provide an extra boundary condition which helps determine the unknown distribution function. A simple perturbation approximation is derived and used to solve this inverse problem and thus obtain estimates of the spatial distribution of CNG ion channels along the length of a cilium. A one-dimensional computer minimization and a special delay iteration are used with the perturbation formulas to obtain approximate channel distributions in the cases of simulated and experimental data.