Kinetics and mechanisms of catalyzed dual-E (antithetic) controllers

Homeostasis plays a central role in our understanding how cells and organisms are able to oppose environmental disturbances and thereby maintain an internal stability. During the last two decades there has been an increased interest in using control engineering methods, especially integral control, in the analysis and design of homeostatic networks. Several reaction kinetic mechanisms have been discovered which lead to integral control. In two of them integral control is achieved, either by the removal of a single control species E by zero-order kinetics (“single-E controllers”), or by the removal of two control species by second-order kinetics (“antithetic or dual-E control”). In this paper we show results when the control species E1 and E2 in antithetic control are removed enzymatically by ping-pong or ternary-complex mechanisms. Our findings show that enzyme-catalyzed dual-E controllers can work in two control modes. In one mode, one of the two control species is active, but requires zero-order kinetics in its removal. In the other mode, both controller species are active and both are removed enzymatically. Conditions for the two control modes are put forward and biochemical examples with the structure of enzyme-catalyzed dual-E controllers are discussed.publishedVersio

An amplified derepression controller with multisite inhibition and positive feedback

How organisms are able to maintain robust homeostasis has in recent years received increased attention by the use of combined control engineering and kinetic concepts, which led to the discovery of robust controller motifs. While these motifs employ kinetic conditions showing integral feedback and homeostasis for step-wise perturbations, the motifs’ performance differ significantly when exposing them to time dependent perturbations. One type of controller motifs which are able to handle exponentially and even hyperbolically growing perturbations are based on derepression. In these controllers the compensatory reaction, which neutralizes the perturbation, is derepressed, i.e. its reaction rate is increased by the decrease of an inhibitor acting on the compensatory flux. While controllers in this category can deal well with different time-dependent perturbations they have the disadvantage that they break down once the concentration of the regulatory inhibitor becomes too low and the compensatory flux has gained its maximum value. We wondered whether it would be possible to bypass this restriction, while still keeping the advantages of derepression kinetics. In this paper we show how the inclusion of multisite inhibition and the presence of positive feedback loops lead to an amplified controller which is still based on derepression kinetics but without showing the breakdown due to low inhibitor concentrations. By searching for the amplified feedback motif in natural systems, we found it as a part of the plant circadian clock where it is highly interlocked with other feedback loops.publishedVersio

Molecular Dynamic Simulations of Biological Membranes

Biological membranes mainly constituent lipid molecules along with some proteins and steroles. The properties of the pure lipid bilayers as well as in the presence of other constituents (in case of two or three component systems) are very important to be studied carefully to model these systems and compare them with the realistic systems. Molecular dynamic simulations provide a good opportunity to model such systems and to study them at microscopic level where experiments fail to do. In this thesis we study the structural and dynamic properties of the pure phospholipid bilayers and the phase behavior of phospholipid bilayers when other constituents are present in them. Material and structural properties like area per lipid and area compressibility of the phospholipids show a big scatter in experiments. These properties are studied for different system sizes and it was found that the increasing undulations in large systems effect these properties. A correction was applied to area per lipid and area compressibility using the Helfrich theory in Fourier space. Other structural properties like order of the lipid chains, electron density and radial distribution functions are calculated which give the structure of the lipid bilayer along the normal and in the lateral direction. These properties are compared to the X-ray and neutron scattering experiments after Fourier transform. Thermodynamic properties like heat capacity and heat of melting are also calculated from derivatives of energies available in molecular dynamics. Heat capacity on the other hand include quantum effect and are corrected for that by applying quantum correction using normal mode analysis for a simple as well as ambiguous system like water. Here it is done for SPC/E water model. The purpose of this study is to further apply the quantum corrections on macromolecules like lipids by using this technique. Furthermore the phase behavior of two component systems (phospholipids/cholesterol) is also studied. Phase transition in these systems is observed at different cholesterol concentrations as a function of temperature by looking at different quantities (as an order parameter) like the order of chains, area per molecule and partial specific area. Radial distribution functions are used to look at the in plane structure for different phases having a different lateral or positional order. Adding more cholesterol orders the lipid chains changing a liquid disordered system into a liquid ordered one and turning a solid ordered system into a liquid ordered one. Further more the free energy of domain formation is calculated to investigate the two phasecoexistence in binary systems. Free energy contains two terms. One is bulk freeenergy which was calculated by the chemical potential of cholesterol moleculein a homogeneous system which is favorable for segregation. Second is thefree energy of having an interface which is calculated from the line tension of the interface of two systems with different cholesterol concentration which in unfavorable for domain formation. The size of the domains calculated from these two contributions to the free energy gives the domains of a few nm in size. Though we could not find any such domains by directly looking at our simulations.QC 20120913</p

Molecular Dynamic Simulations of Biological Membranes

Biological membranes mainly constituent lipid molecules along with some proteins and steroles. The properties of the pure lipid bilayers as well as in the presence of other constituents (in case of two or three component systems) are very important to be studied carefully to model these systems and compare them with the realistic systems. Molecular dynamic simulations provide a good opportunity to model such systems and to study them at microscopic level where experiments fail to do. In this thesis we study the structural and dynamic properties of the pure phospholipid bilayers and the phase behavior of phospholipid bilayers when other constituents are present in them. Material and structural properties like area per lipid and area compressibility of the phospholipids show a big scatter in experiments. These properties are studied for different system sizes and it was found that the increasing undulations in large systems effect these properties. A correction was applied to area per lipid and area compressibility using the Helfrich theory in Fourier space. Other structural properties like order of the lipid chains, electron density and radial distribution functions are calculated which give the structure of the lipid bilayer along the normal and in the lateral direction. These properties are compared to the X-ray and neutron scattering experiments after Fourier transform. Thermodynamic properties like heat capacity and heat of melting are also calculated from derivatives of energies available in molecular dynamics. Heat capacity on the other hand include quantum effect and are corrected for that by applying quantum correction using normal mode analysis for a simple as well as ambiguous system like water. Here it is done for SPC/E water model. The purpose of this study is to further apply the quantum corrections on macromolecules like lipids by using this technique. Furthermore the phase behavior of two component systems (phospholipids/cholesterol) is also studied. Phase transition in these systems is observed at different cholesterol concentrations as a function of temperature by looking at different quantities (as an order parameter) like the order of chains, area per molecule and partial specific area. Radial distribution functions are used to look at the in plane structure for different phases having a different lateral or positional order. Adding more cholesterol orders the lipid chains changing a liquid disordered system into a liquid ordered one and turning a solid ordered system into a liquid ordered one. Further more the free energy of domain formation is calculated to investigate the two phasecoexistence in binary systems. Free energy contains two terms. One is bulk freeenergy which was calculated by the chemical potential of cholesterol moleculein a homogeneous system which is favorable for segregation. Second is thefree energy of having an interface which is calculated from the line tension of the interface of two systems with different cholesterol concentration which in unfavorable for domain formation. The size of the domains calculated from these two contributions to the free energy gives the domains of a few nm in size. Though we could not find any such domains by directly looking at our simulations.QC 20120913</p

DOPA Homeostasis by Dopamine: A Control-Theoretic View

Dopamine (DA) is an important signal mediator in the brain as well as in the periphery. The term “dopamine homeostasis” occasionally found in the literature refers to the fact that abnormal DA levels can be associated with a variety of neuropsychiatric disorders. An analysis of the negative feedback inhibition of tyrosine hydroxylase (TH) by DA indicates, with support from the experimental data, that the TH-DA negative feedback loop has developed to exhibit 3,4-dihydroxyphenylalanine (DOPA) homeostasis by using DA as a derepression regulator. DA levels generally decline when DOPA is removed, for example, by increased oxidative stress. Robust DOPA regulation by DA further implies that maximum vesicular DA levels are established, which appear necessary for a reliable translation of neural activity into a corresponding chemical transmitter signal. An uncontrolled continuous rise (windup) in DA occurs when Levodopa treatment exceeds a critical dose. Increased oxidative stress leads to the successive breakdown of DOPA homeostasis and to a corresponding reduction in DA levels. To keep DOPA regulation robust, the vesicular DA loading requires close to zero-order kinetics combined with a sufficiently high compensatory flux provided by TH. The protection of DOPA and DA due to a channeling complex is discussed.publishedVersio

DOPA Homeostasis by Dopamine: A Control-Theoretic View

Dopamine (DA) is an important signal mediator in the brain as well as in the periphery. The term “dopamine homeostasis” occasionally found in the literature refers to the fact that abnormal DA levels can be associated with a variety of neuropsychiatric disorders. An analysis of the negative feedback inhibition of tyrosine hydroxylase (TH) by DA indicates, with support from the experimental data, that the TH-DA negative feedback loop has developed to exhibit 3,4-dihydroxyphenylalanine (DOPA) homeostasis by using DA as a derepression regulator. DA levels generally decline when DOPA is removed, for example, by increased oxidative stress. Robust DOPA regulation by DA further implies that maximum vesicular DA levels are established, which appear necessary for a reliable translation of neural activity into a corresponding chemical transmitter signal. An uncontrolled continuous rise (windup) in DA occurs when Levodopa treatment exceeds a critical dose. Increased oxidative stress leads to the successive breakdown of DOPA homeostasis and to a corresponding reduction in DA levels. To keep DOPA regulation robust, the vesicular DA loading requires close to zero-order kinetics combined with a sufficiently high compensatory flux provided by TH. The protection of DOPA and DA due to a channeling complex is discussed