Parameter adaptations during phenotype transitions in progressive diseases

<p>Abstract</p> <p>Background</p> <p>The study of phenotype transitions is important to understand progressive diseases, e.g., diabetes mellitus, metabolic syndrome, and cardiovascular diseases. A challenge remains to explain phenotype transitions in terms of adaptations in molecular components and interactions in underlying biological systems.</p> <p>Results</p> <p>Here, mathematical modeling is used to describe the different phenotypes by integrating experimental data on metabolic pools and fluxes. Subsequently, trajectories of parameter adaptations are identified that are essential for the phenotypical changes. These changes in parameters reflect progressive adaptations at the transcriptome and proteome level, which occur at larger timescales. The approach was employed to study the metabolic processes underlying liver X receptor induced hepatic steatosis. Model analysis predicts which molecular processes adapt in time after pharmacological activation of the liver X receptor. Our results show that hepatic triglyceride fluxes are increased and triglycerides are especially stored in cytosolic fractions, rather than in endoplasmic reticulum fractions. Furthermore, the model reveals several possible scenarios for adaptations in cholesterol metabolism. According to the analysis, the additional quantification of one cholesterol flux is sufficient to exclude many of these hypotheses.</p> <p>Conclusions</p> <p>We propose a generic computational approach to analyze biological systems evolving through various phenotypes and to predict which molecular processes are responsible for the transition. For the case of liver X receptor induced hepatic steatosis the novel approach yields information about the redistribution of fluxes and pools of triglycerides and cholesterols that was not directly apparent from the experimental data. Model analysis provides guidance which specific molecular processes to study in more detail to obtain further understanding of the underlying biological system.</p

The role of collagen in bone apatite formation in the presence of hydroxyapatite nucleation inhibitors

Bone is a composite material in which collagen fibrils form a scaffold for a highly organized arrangement of uniaxially oriented apatite crystals. In the periodic 67¿nm cross-striated pattern of the collagen fibril, the less dense 40-nm-long gap zone has been implicated as the place where apatite crystals nucleate from an amorphous phase, and subsequently grow. This process is believed to be directed by highly acidic non-collagenous proteins, however, the role of the collagen matrix during bone apatite mineralization remains unknown. Here, combining nanometre-scale resolution cryogenic transmission electron microscopy and cryogenic electron tomography with molecular modelling, we show that collagen functions in synergy with inhibitors of hydroxyapatite nucleation to actively control mineralization. The positive net charge close to the C-terminal end of the collagen molecules promotes the infiltration of the fibrils with amorphous calcium phosphate (ACP). Furthermore, the clusters of charged amino acids, both in gap and overlap regions, form nucleation sites controlling the conversion of ACP into a parallel array of oriented apatite crystals. We developed a model describing the mechanisms through which the structure, supramolecular assembly and charge distribution of collagen can control mineralization in the presence of inhibitors of hydroxyapatite nucleatio

Computation of accommodation coefficients and the use of velocity correlation profiles in molecular dynamics simulations

For understanding the behavior of a gas close to a channel wall it is important to model the gas-wall interactions as detailed as possible. When using molecular dynamics simulations these interactions can be modeled explicitly, but the computations are time consuming. Replacing the explicit wall with a wall model reduces the computational time but the same characteristics should still remain. Elaborate wall models, such as the Maxwell-Yamamoto model or the Cercignani-Lampis model need a phenomenological parameter (the accommodation coefficient) for the description of the gas-wall interaction as an input. Therefore, computing these accommodation coefficients in a reliable way is very important. In this paper, two systems (platinum walls with either argon or xenon gas confined between them) are investigated and are used for comparison of the accommodation coefficients for the wall models and the explicit molecular dynamics simulations. Velocity correlations between incoming and outgoing particles colliding with the wall have been used to compare explicit simulations and wall models even further. Furthermore, based on these velocity correlations, a method to compute the accommodation coefficients is presented, and these newly computed accommodation coefficients are used to show improved correlation behavior for the wall models

Velocity correlations and accommodation coefficients for gas-wall interactions in nanochannels

\u3cp\u3eIn order to understand the behavior of a gas close to a channel wall, it is important to model the gas-wall interactions correctly. When using Molecular Dynamics (MD) simulations these interactions are modeled explicitly, but the computations are time consuming. Replacing the explicit wall with an appropriate wall model reduces the computational time, but should still remain the same characteristics. In this paper the focus lies with an argon gas confined between two platinum walls at different temperature. Several wall models are investigated for their feasibility as a replacement of the MD simulations and are mainly compared using the velocity correlations between impinging and reflecting particles. Moreover, a new method to compute the accommodation coefficient using the velocity correlations is demonstrated.\u3c/p\u3

Molecular dynamics study of lipid based vesicle fission

Together with vesicle fusion and budding, vesicle fission plays an important role in intracellular traffic. Vesicle fission is known to take place in different ways, either or not instigated by proteins. However, as at a molecular level the dynamics of the cell membrane and the working mechanisms of proteins cannot be readily asserted experimentally, many different hypotheses exist to predict and explain these processes. Therefore, we use coarse grained molecular dynamics simulations to elucidate the fission mechanism of vesicles, where we focus on possible mechanisms in the absence of proteins. Two distinct routes are considered that are both based on an asymmetry of the lipid distribution in the membrane. I n the first mechanism, the two types of lipids are equally distributed over both leaflets of the membrane. However, phase separation of the lipids within both leaflets results in domains which form buds that can split off. I n the second mechanism, the asymmetry consists either of a difference in composition between the two monolayers of the membrane or of a difference between the vesicle interior and exterior. This difference in composition yields a spontaneous curvature of the membrane, reshaping the vesicle into a dumbbell which can split. Both pathways are studied using molecular dynamics simulations of the same coarse grained lipid model that has been used before to study spontaneous bilayer and vesicle formation [1], vesicle fusion [2], and vesicle deformations [3]. Using these simulations, the specific conditions to obtain complete fission are investigated for both pathways

Multivalency in a dendritic host-guest system

\u3cp\u3eMultivalency is an important instrument in the supramolecular chemistry toolkit for the creation of strong specific interactions. In this paper we investigate the multivalency effect in a dendritic host-guest system using molecular dynamics simulations. Specifically, we consider urea-adamantyl decorated poly(propyleneimine) dendrimers that together with compatible mono-, bi-, and tetravalent ureidoacetic acid guests can form dynamic patchy nanoparticles. First, we simulate the self-assembly of these particles into macromolecular nanostructures, showing guest-controlled reduction of dendrimer aggregation. Subsequently, we systematically study guest concentration dependent multivalent binding. At low guest concentrations multivalency of the guests clearly increases relative binding as tethered headgroups bind more often than free guests' headgroups. We find that despite an abundance of binding sites, most of the tethered headgroups bind in close proximity, irrespective of the spacer length; nevertheless, longer spacers do increase binding. At high guest concentrations the dendrimer becomes saturated with bound headgroups, independent of guest valency. However, in direct competition the tetravalent guests prevail over the monovalent ones. This demonstrates the benefit of multivalency at high as well as low concentrations.\u3c/p\u3

The bilayer-vesicle transition is entropy driven

Self-assembled bilayer membranes have a remarkable inclination to form closed shells or vesicles. This bilayer-vesicle transition has been shown experimentally and by various kinds of computer simulation techniques. Here we study this transition using coarse-grained molecular dynamics. The advantage of this simulation technique is that it allows for a detailed analysis of the transition, such as changes of the internal energy. Generally it is assumed that the bilayer-vesicle transition is driven by minimization of the edge energy. However, our simulations, which include solvent particles, show an increase in the potential energy of the system during the transition, implicating that the transition is not energy but entropy driven

An equilibrium model for chiral amplification in supramolecular polymers

We describe a model that rationalizes amplification of chirality in cooperative supramolecular copolymerization. The model extends nucleation-elongation based equilibrium models for growth of supramolecular homopolymers to the case of two monomer and aggregate types. Using the principle of mass-balance for the two monomer types, we derive a set of two nonlinear equations, describing the thermodynamic equilibrium state of the system. These equations can be solved by numerical methods, but also analytical approximations are derived. The equilibrium model allows two-sided growth of the aggregates and can be applied to symmetric supramolecular copolymerizations, corresponding to the situation in which the monomers are enantiomerically related, as well as to the more general case of nonsymmetric supramolecular copolymerizations. In detail, so-called majority-rules phenomena in supramolecular systems with isodesmic as well as cooperative growth are analyzed. Comparison of model predictions with experimental data shows that the model gives a very good description of both titration and melting curves. When the system shows cooperative growth, the model leads to a phase diagram in which the presence of the various aggregate types is given as a function of composition and temperature

Molecular simulation of protein encapsulation in vesicle formation

Liposomes composed of fatty acids and phospholipids are frequently used as model systems for biological cell membranes. In many applications, the encapsulation of proteins and other bio-macromolecules in these liposomes is essential. Intriguingly, the concentration of entrapped material often deviates from that in the solution where the liposomes were formed in. While some reports mention reduced concentrations inside the vesicles, concentrations are also reported to be enhanced in other cases. To elucidate possible drivers for efficient encapsulation, we here investigate the encapsulation of model proteins in spontaneously forming vesicles using molecular dynamics simulations with a coarse grained force field for fatty acids, phospholipids as well as water-soluble and transmembrane proteins. We show that, in this model system, the encapsulation efficiency is dominated by the interaction of the proteins with the membrane, while no significant dependence is observed on the size of the encapsulated proteins nor on the speed of the vesicle formation, whether reduced by incorporation of stiff transmembrane proteins or by the blocking of the bilayer bulging by the presence of another membrane