Institute of Complex Systems
Institute of Complex Systems
Abrahamsen B.,Copenhagen University |
Schneider N.,Institute For Neurophysiologie |
Schneider N.,Institute of Complex Systems |
Erichsen M.N.,Copenhagen University |
And 5 more authors.
Journal of Neuroscience | Year: 2013
In the present study, the mechanism of action and molecular basis for the activity of the first class of selective inhibitors of the human excitatory amino acid transporter subtype 1 (EAAT1) and its rodent ortholog GLAST are elucidated. The previously reported specificity of UCPH-101 and UCPH-102 for EAAT1 over EAAT2 and EAAT3 is demonstrated to extend to the EAAT4 and EAAT5 subtypes as well. Interestingly, brief exposure to UCPH-101 induces a long-lasting inactive state of EAAT1, whereas the inhibition exerted by closely related analogs is substantially more reversible in nature. In agreement with this, the kinetic properties of UCPH-101 unblocking of the transporter are considerably slower than those of UCPH-102. UCPH-101 exhibits noncompetitive inhibition of EAAT1, and its binding site in GLAST has been delineated in an elaborate mutagenesis study. Substitutions of several residues in TM3, TM4c, and TM7a of GLAST have detrimental effects on the inhibitory potency and/or efficacy of UCPH-101 while not affecting the pharmacological properties of (S)- glutamate or the competitive EAAT inhibitor TBOA significantly. Hence, UCPH-101 is proposed to target a predominantly hydrophobic crevice in the "trimerization domain" of the GLAST monomer, and the inhibitor is demonstrated to inhibit the uptake through the monomer that it binds to exclusively and not to affect substrate translocation through the other monomers in the GLAST trimer. The allosteric mode of UCPH-101 inhibition underlines the functional importance of the trimerization domain of the EAAT and demonstrates the feasibility of modulating transporter function through ligand binding to regions distant from its "transport domain.". © 2013 the authors.
News Article | January 18, 2016
In experiments and computer simulations, researchers repeatedly deformed red blood cells, let them “wriggle” and then analysed their behaviour. Three tiny spheres hold the cells in place during the process, while the movements of the cell membrane are measured with the help of a fourth sphere. The “wrapper” of the blood cell consists of a lipid double layer and a cytoskeleton; active forces, produced for example by an ion pump, move the membrane (red arrows) and fluids (green arrows) locally in opposite directions. Credit: Forschungszentrum Jülich For the first time, and using physical methods, scientists have demonstrated how red blood cells move. There had been real fights between academics over the question of whether these cells are moved by external forces or whether they actively "wriggle". An international team of biophysicists from Münster, Paris and Jülich have now proven that both opinions are correct. Linking physical principles and biological reality, they recognized that fast molecules in the vicinity make the cell membrane of the blood cells wriggle – but that the cells themselves also become active when they have enough reaction time. This process can be defined exactly by comparing innovative experiments with new theoretical models. The study was published in Nature Physics. The function of red blood cells (erythrocytes) is to transport oxygen in the blood of vertebrates. Up to now, scientists had only seen the reason for their constant wriggling in thermal (i.e. external) forces. On the other hand, biological considerations suggest that internal forces caused by proteins are also responsible for the cell membrane in blood cells changing its shape. "So we started with the following question: As blood cells are living cells, why shouldn't internal forces inside the cell also have an impact on the membrane?" says Dr. Timo Betz from Münster University. "For biologists, this is all clear – but these forces were just never a part of any physical equation." The researchers even have a suspicion already as to which forces inside the cell cause the cell membrane to change shape. "Transport proteins could generate such forces in the membrane by moving ions from one side of the membrane to the other," says Prof. Gerhard Gompper, a Director at the Jülich Institute of Complex Systems. Timo Betz has been doing research as a biophysicist at Münster University since 2015 and is head of the Mechanics of Cellular Systems research group within the Excellence Cluster "Cells in Motion". Research into the activity of red blood cells started as an international collaboration between the prestigious Institut Curie in Paris and two institutes in Jülich – the Institute of Complex Systems and the Institute for Advanced Simulation – and the work has now been completed in Münster, Paris and Jülich. "The key to our success was the interaction of Hervé Turlier's physical theories, the computer simulations made by Dmitry Fedosov and Thorsten Auth, and my experimental results," Timo Betz explains. The combination of experimental work, theory and computer simulations is essential for gaining new insights, says Gerhard Gompper. "Nowadays, modern simulations are able to quantify chemical and biological processes which do not lend themselves to direct experimental observation," he adds. The researchers want to find out more about the mechanics of blood cells and gain a detailed understanding of the forces which move and shape cells. In the case of red cells in particular, it is important to know precisely about their properties and their internal forces – because they are unusually soft and elastic and change their shape in order to be able to pass through the sometimes minute blood vessels in our body. It is precisely because blood cells are normally so soft that, in previous studies, physicists measured large thermal fluctuations at the outer membrane of the cells. These natural movements of molecules are defined by the ambient temperature. In other words, the cell membrane of the blood cells moves because molecules in the vicinity jog it. Under the microscope, this makes the blood cells appear to be wriggling. Although this explains why blood cells move, it does not address the question of possible internal forces being a contributory factor. So the research team led by Timo Betz has been using a new method to take a close look at the fluctuations of blood cells. Using so-called optical tweezers – a concentrated laser beam – the researchers stretched blood cells in a petri dish and analysed the behaviour of the cell. The result was that if the blood cells had enough reaction time they became active themselves and were able to counteract the force of the optical tweezers. If they did not have this time, they were at the mercy of their environment, and only temperature-related forces were measured. "By comparing both sets of measurements we can exactly define how fast the cells become active themselves and what force they generate in order to change shape," Betz explains. "Now it's up to the biologists, because we physicists only have a rough idea about which proteins might be the drivers for this movement. On the other hand, we can predict exactly how fast and how strong they are." Explore further: Putting the squeeze on a cell's nucleus More information: H. Turlier et al. Equilibrium physics breakdown reveals the active nature of red blood cell flickering, Nature Physics (2016). DOI: 10.1038/NPHYS3621
Chelakkot R.,Institute of Complex Systems |
Chelakkot R.,Brandeis University |
Winkler R.G.,Institute of Complex Systems |
Gompper G.,Institute of Complex Systems
Physical Review Letters | Year: 2012
The conformations of semiflexible (bio)polymers are studied in flow-through geometrically structured microchannels. Using mesoscale hydrodynamics simulations, we show that the polymer undergoes a rod-to-helix transition as it moves from the narrow high-velocity region into the wide low-velocity region of the channel. The transient helix formation is the result of a nonequilibrium and nonstationary buckling transition of the semiflexible polymer, which is subjected to a compressive force originating from the fluid-velocity variation in the channel. The helix properties depend on the diameter ratio of the channel, the polymer bending rigidity, and the flow strength. © 2012 American Physical Society.
Estrada E.,Institute of Complex Systems |
Hatano N.,University of Tokyo
Physica A: Statistical Mechanics and its Applications | Year: 2010
We propose a new measure of vulnerability of a node in a complex network. The measure is based on the analogy in which the nodes of the network are represented by balls and the links are identified with springs. We define the measure as the node displacement, or the amplitude of vibration of each node, under fluctuation due to the thermal bath in which the network is supposed to be submerged. We prove exact relations among the thus defined node displacement, the information centrality and the Kirchhoff index. The relation between the first two suggests that the node displacement has a better resolution of the vulnerability than the information centrality, because the latter is the sum of the local node displacement and the node displacement averaged over the entire network. © 2010 Elsevier B.V. All rights reserved.
Estrada E.,Institute of Complex Systems |
Hatano N.,University of Tokyo
Chemical Physics Letters | Year: 2010
We provide a physical interpretation of the Kirchhoff index of any molecules as well as of the Wiener index of acyclic ones. For the purpose, we use a local vertex invariant that is obtained from first principles and describes the atomic displacements due to small vibrations/oscillations of atoms from their equilibrium positions. In addition, we show that the topological atomic displacements correlate with the temperature factors (B-factors) of atoms obtained by X-ray crystallography for both organic molecules and biological macromolecules. © 2009 Elsevier B.V. All rights reserved.
Estrada E.,Institute of Complex Systems
Journal of Theoretical Biology | Year: 2010
A strategy for zooming in and out the topological environment of a node in a complex network is developed. This approach is applied here to generalize the subgraph centrality of nodes in complex networks. In this case the zooming in strategy is based on the use of some known matrix functions which allow focusing locally on the environment of a node. When a zooming out strategy is applied new matrix functions are introduced, which give a more global picture of the topological surrounds of a node. These indices permit a modulation of the scales at which the environment of a node influences its centrality. We apply them to the study of 10 protein-protein interaction (PPI) networks. We illustrate the similarities and differences between the generalized subgraph centrality indices as well as among them and some classical centrality measures. We show here that the use of centrality indices based on the zooming in strategy identifies a larger number of essential proteins in the yeast PPI network than any of the other centrality measures studied. © 2010 Elsevier Ltd. All rights reserved.
Poblete S.,Institute of Complex Systems |
Wysocki A.,Institute of Complex Systems |
Gompper G.,Institute of Complex Systems |
Winkler R.G.,Institute of Complex Systems
Physical Review E - Statistical, Nonlinear, and Soft Matter Physics | Year: 2014
We investigate the hydrodynamic properties of a spherical colloid model, which is composed of a shell of point particles by hybrid mesoscale simulations, which combine molecular dynamics simulations for the sphere with the multiparticle collision dynamics approach for the fluid. Results are presented for the center-of-mass and angular velocity correlation functions. The simulation results are compared with theoretical results for a rigid colloid obtained as a solution of the Stokes equation with no-slip boundary conditions. Similarly, analytical results of a point-particle model are presented, which account for the finite size of the simulated system. The simulation results agree well with both approaches on appropriative time scales; specifically, the long-time correlations are quantitatively reproduced. Moreover, a procedure is proposed to obtain the infinite-system-size diffusion coefficient based on a combination of simulation results and analytical predictions. In addition, we present the velocity field in the vicinity of the colloid and demonstrate its close agreement with the theoretical prediction. Our studies show that a point-particle model of a sphere is very well suited to describe the hydrodynamic properties of spherical colloids, with a significantly reduced numerical effort. © 2014 American Physical Society.
Wysocki A.,Institute of Complex Systems |
Elgeti J.,Institute of Complex Systems |
Gompper G.,Institute of Complex Systems
Physical Review E - Statistical, Nonlinear, and Soft Matter Physics | Year: 2015
The effect of shape asymmetry of microswimmers on their adsorption capacity at confining channel walls is studied by a simple dumbbell model. For a shape polarity of a forward-swimming cone, like the stroke-averaged shape of a sperm, extremely long wall retention times are found, caused by a nonvanishing component of the propulsion force pointing steadily into the wall, which grows exponentially with the self-propulsion velocity and the shape asymmetry. A direct duality relation between shape asymmetry and wall curvature is proposed and verified. Our results are relevant for the design microswimmer with controlled wall-adhesion properties. In addition, we confirm that pressure in active systems is strongly sensitive to the details of the particle-wall interactions. © 2015 American Physical Society.
News Article | March 23, 2016
Superimposed stages of the movement of a LOV protein (foreground), generated by molecular dynamic simulation. The red areas show the initial position; the blue indicates the final position. A functional unit is made up of two LOV domains - the second can be seen in the background as the semi-transparent image. The light-absorbing centres of the protein are depicted in both subunits as ball-and-stick models. Credit: Forschungszentrum Jülich/M. Bocola, RWTH Aachen The internal movements of proteins can be important for their functionality; researchers are discovering more and more examples of this. Now, with the aid of neutron spectroscopy, dynamic processes have also been detected in so-called "LOV photoreceptors" by scientists from Jülich, Aachen, Dusseldorf and Garching near Munich. These proteins are widely distributed throughout nature and are of biotechnological relevance. The results highlight the immense potential of neutron scattering experiments for the analysis of cellular processes. The research has recently been published in the Biophysical Journal. OV proteins are very popular with molecular biologists; with their help, it is possible to turn biological processes on and off almost at the flick of a switch. When coupled with other proteins, it is possible to control these proteins with light, and to study the metabolic processes in the modified cells. The rather emotional-sounding name of this biological switch has a mundane origin; it is merely an acronym for light, oxygen and voltage – its full name being "flavin-binding light, oxygen, voltage photoreceptor". In nature, light-sensitive protein molecules stimulate biological processes, for example, the growth of plants towards light and the production of photosynthesis pigments in bacteria, when light falls on them. Their wide distribution in nature and their technological usefulness result partly from the fact that they function in a modular way: the switching function can be combined with many other processes. The first experiments on LOV proteins using neutron scattering at the Heinz Maier-Leibnitz Zentrum in Garching have now shown the importance of the internal movements of these biomolecules for their functionality. The scientists analysed one such receptor from the soil bacterium Pseudomonas putida with a temporal resolution on the nano- and picosecond timescales. "We found more intense movements in unexposed proteins than in those exposed to light", explained Dr. Andreas Stadler of the Institute of Complex Systems and Jülich Centre for Neutron Science at Forschungszentrum Jülich. "The exposed version is stiffer, especially in certain specific areas." In order to find out which areas of the protein are in motion, the researchers compared their neutron analyses with structural information already obtained from X-ray experiments with crystallized LOV proteins, and then simulated possible movements on a computer. This was necessary because neutrons are not able to register the movements of individual parts of protein molecules, but only the averaged movements of all proteins in the sample. For this reason, further experiments are always needed to ensure the correct interpretation of results. "If used appropriately, as in this case, neutrons can demonstrate their full capabilities and provide unique insights into the functions of biological processes," enthused Stadler. In the case of the LOV proteins analysed, it was already understood that two protein molecules would together form a functional unit. Their shape, in an active exposed state, looks a little like a rabbit's head with pointed ears. In their non-active, non-exposed state, the "rabbit ears" hang downwards. The movements which the researchers have now discovered in the non-exposed proteins coincide exactly with the idea that this state is more flexible and mobile, whereas the upright "ears" are indeed stiffer and more rigid. From earlier experiments, it was also already clear that the light-active centre was located in the "cheek" area of the protein's "rabbit head". On exposure to light, a chemical bond results between the light-active centre and a particular position on the protein backbone. The scientists now assume that the creation of this bond leads to structural alterations, which spread through the protein up to the "ears", triggering their stiffening and simultaneous twisting. The "ears" presumably constitute the actual switch, which can activate or deactivate the interconnected proteins. Neutrons offer numerous advantages over other methods in the analysis of proteins, and can provide significant complementary information. Proteins do not have to be dyed, crystallized, or altered in any way in order to perform experiments on them. Moreover, the process is very gentle on the samples, which can then be observed for longer time periods. Last but not least, light atoms in molecules such as hydrogen, for instance, can be detected more easily, even in the natural environment of proteins – aqueous solutions. Explore further: How water molecules dance to activate proteins More information: Andreas M. Stadler et al. Photoactivation Reduces Side-Chain Dynamics of a LOV Photoreceptor, Biophysical Journal (2016). DOI: 10.1016/j.bpj.2016.01.021
News Article | December 20, 2016
Many biological processes in cells function solely due to the phenomenon of diffusion. This ensures that particles are able to move randomly and aimlessly on the basis of their thermal energy alone. In this way, protein molecules get into close enough proximity to each other to, for example, carry out metabolic processes only achievable when acting together. A team of international researchers has now shown that weak attraction forces between proteins can enormously influence diffusion, if the protein molecules are as densely concentrated as under natural conditions in living cells. Read more on the homepage of the Institute of Complex Systems, an institute of Forschungszentrum Jülich: http://www. Here we provide an overview of more selected papers by Jülich scientists that have been published in journals. These notifications comprise a brief summary as well as data regarding the publication: http://www.