Coarse Grained Molecular Dynamics Simulations of Transmembrane Protein-Lipid Systems

Many biological cellular processes occur at the micro- or millisecond time scale. With traditional all-atom molecular modeling techniques it is difficult to investigate the dynamics of long time scales or large systems, such as protein aggregation or activation. Coarse graining (CG) can be used to reduce the number of degrees of freedom in such a system, and reduce the computational complexity. In this paper the first version of a coarse grained model for transmembrane proteins is presented. This model differs from other coarse grained protein models due to the introduction of a novel angle potential as well as a hydrogen bonding potential. These new potentials are used to stabilize the backbone. The model has been validated by investigating the adaptation of the hydrophobic mismatch induced by the insertion of WALP-peptides into a lipid membrane, showing that the first step in the adaptation is an increase in the membrane thickness, followed by a tilting of the peptide

Property indices : Extrapolation of the IPD Japan Capital Growth Index

The aim of this work is to extrapolate the IPD Japan Capital Growth index series historically back to the early 1980’s. Using existing, long-running, macro-economic and property-related time series as inputs, we will try to set up a statistical model which can extrapolate the existing eight-year track record back for as many years as statistically significant. Our aim is to set up a model which allows us to produce a historical real estate capital growth series going back for 15 to 20 year

Multi-scale coarse graining and molecular dynamics simulations of vesicle formation

The basic mechanisms of living cells have attracted an increased interest in recent years, triggered perhaps by the prospect of creating life in the laboratory through synthetic biology. This once-futuristic idea has become realistic through scientific progress in the past decade. One of the main challenges in current synthetic biology is the design of a so-called "minimal cell", a cell with only those parts which are essential for its survival. An important feature of such a minimal cell is its casing, as a boundary with the environment. Amphiphilic, self-aggregating molecules such as phospholipids and fatty acids may form a membrane to serve as such a casing, in the shape of spontaneously formed spherical vesicles. To understand the self-aggregation behavior of these membrane components, it is important to understand their molecular properties and the intermolecular interactions. However, not all of these properties can be observed experimentally, which has lead to the use of in silico methods, such as molecular modeling, in which molecular systems are represented by computational models. A frequently used technique to model the dynamic behavior of a system is molecular dynamics, where successive configurations are generated by integrating Newton’s laws of motion. Molecular dynamics may be used with detailed atomistic models, but also with so-called coarse grained models, where groups of atoms are represented by single coarse grained particles. Coarse grained models are often employed to study systems with longer time and length scales, for which the calculation time in an atomistic representation is unfeasibly long. However, in coarse grained modeling it can be challenging to find suitable model parameters. Therefore, in our work we develop a new coarse graining method. Furthermore, we employ (coarse grained) molecular dynamics to investigate the properties of lipid membranes. In the first part of this thesis, we introduce a novel method to coarse grain an atomistic simulation, the CUMULUS coarse graining method. Combined with the iterative Boltzmann inversion procedure, this coarse graining method can be employed to derive coarse grained force fields in a "multi-scale" approach, in order to reproduce structural properties from simulations at the atomistic level. This approach is applied on systems containing pure water, sodium chloride solutions, and water–octanol mixtures. Also, the CUMULUS method is tested on two systems containing larger molecules, poly-norbornene in chloroform and a poly(propylene imine) dendrimer in water. Importantly, the obtained force fields are found to be transferable to systems of different composition. Having developed this method, we investigate the role of protonation in the behavior of oleic acid vesicles. First, in an atomistic simulation of a periodic oleic acid membrane, a strong hydrogen bonding network between protonated and deprotonated species of oleic acid is observed. Next, a coarse grained oleic acid model is constructed with the CUMULUS coarse graining method and the iterative Boltzmann inversion procedure. In this model, two different headgroup types are used to represent the protonated and deprotonated species of the molecules. Although this model is parametrized successfully, the phase behavior of the coarse grained oleic acid membranes does not match that of experiments. The second part of this thesis is aimed at understanding the behavior of lipid vesicles and their encapsulation of biomacromolecules. We employ an existing coarse grained model of lipids and water to perform simulations of the spontaneous transition of a flat bilayer to a spherical vesicle. Our investigations reveal that this transition follows a molecular pathway we denominate "bilayer bulging". Our analysis indicates that the inward forces exerted by the solvent on the edge of the membrane are the main driving force behind this bilayer bulging pathway. Upon addition of water-soluble proteins to these simulations, it is found that variation of the nonbonded interaction between the proteins and the membrane surface significantly affects the encapsulation efficiency. When the protein–membrane interaction is neutral, the encapsulated protein concentration is below that of the solution. Increasing this interaction results in an increase of the encapsulation efficiency to values above those of the solution, with a linear relationship between the encapsulation efficiency and the strength of adhesion of the proteins to the membrane surface. Furthermore, our simulations indicate that the protein encapsulation efficiency does not depend on the size of the proteins nor on the speed of vesicle formation. In this work we have extended the toolbox of coarse grained molecular modeling and designed new simulations to study lipid membranes. Furthermore, we have investigated the properties of lipid membranes at the molecular level and gained insight into the formation of vesicles and their encapsulation of proteins. Our findings help to construct the required theoretical framework to understand the behavior of lipid membranes in their application as cell membranes for artificial cells

Development of methods for the determination of pK\u3csub\u3ea\u3c/sub\u3e values

\u3cp\u3eThe acid dissociation constant (pK\u3csub\u3ea\u3c/sub\u3e) is among the most frequently used physicochemical parameters, and its determination is of interest to a wide range of research fields. We present a brief introduction on the conceptual development of pK\u3csub\u3ea\u3c/sub\u3e as a physical parameter and its relationship to the concept of the pH of a solution. This is followed by a general summary of the historical development and current state of the techniques of pK\u3csub\u3ea\u3c/sub\u3e determination and an attempt to develop determination and an attempt to develop insight into future developments. Fourteen methods of determining the acid dissociation constant are placed in context and are critically evaluated to make a fair comparison and to determine their applications in modern chemistry. Additionally, we have studied these techniques in light of present trends in science and technology and attempt to determine how these trends might affect future developments in the field.\u3c/p\u3

The Role of Reflection in the Effects of Community Service on Adolescent Development: A Meta-Analysis

This meta-analysis assessed the effect of community service on adolescent development and the moderation of this effect by reflection, community service, and adolescent characteristics to explicate the mechanisms underlying community service effects. Random effects analyses, based on 49 studies (24,477 participants, 12-20 years old), revealed that community service had positive effects on academic, personal, social, and civic outcomes. Moderation analyses indicated that reflection was essential; the effect for studies that include reflection was substantial (mean ES = .41) while community service in the absence of reflection yielded negligible benefits (mean ES = .05). Effects increased when studies include more frequent reflection and community service, reflection on academic content, and older adolescents. These findings have implications for understanding and improving community service

The Role of Reflection in the Effects of Community Service on Adolescent Development : A Meta-Analysis

This meta-analysis assessed the effect of community service on adolescent development and the moderation of this effect by reflection, community service, and adolescent characteristics to explicate the mechanisms underlying community service effects. Random effects analyses, based on 49 studies (24,477 participants, 12-20 years old), revealed that community service had positive effects on academic, personal, social, and civic outcomes. Moderation analyses indicated that reflection was essential; the effect for studies that include reflection was substantial (mean ES = .41) while community service in the absence of reflection yielded negligible benefits (mean ES = .05). Effects increased when studies include more frequent reflection and community service, reflection on academic content, and older adolescents. These findings have implications for understanding and improving community service

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