Exploring the boundaries of molecular modeling : a study of nanochannels and transmembrane proteins

Many interesting physical and biological phenomena can be investigated using molecular modeling techniques, either theoretically or by using computer simulation methods, such as molecular dynamics and Monte Carlo simulations. Due to the increasing power of computer processing units, these simulation methods allowed over the last decades for the dramatic increase in knowledge of the behavior of systems at the molecular level. In the first part of this thesis the foundations of molecular modeling techniques are revisited. Empirical force fields and the physical background between thermodynamics and individual particles are discussed. The applicability of molecular modeling techniques is shown by two representative cases. First, the molecular dynamics simulation method is used to understand the dynamics of specific proteins at the molecular level. This is important, because drug design efforts are increasingly laborious, especially with the paucity of available structural information. Therefore, computational methods are helpful in predicting the structure of proteins, and, more importantly, to predict conformational dynamics leading to protein activation. To that end a specific asthma-related protein, the beta2-adrenergic receptor, is investigated in atomistic detail together with the molecules that can bind to the protein to cause activation or inhibition. Clearly, molecular dynamics simulations are an important tool to provide further knowledge on the activation pathway of this protein. Although these all-atom simulations give some insight on the dynamics, the computational demand does not allow for systems much larger than several nanometers or time scales exceeding several nanoseconds. An attempt to overcome these problems is presented by the development of a coarse grained description of the transmembrane proteins. Because coarse graining reduces the number of degrees of freedom, the computational demands decrease, and larger systems can be investigated. However, to maintain the specific characteristics of transmembrane proteins, the general force field used in molecular modeling techniques needs to be extended with hydrogen bonding capabilities and helical backbone stabilization. This new coarse grained model is applicable to transmembrane proteins, and is used to investigate two independent cases: WALP-peptides and antimicrobial peptides. The first serve as a model system for both experiments and theory to investigate the interaction between transmembrane peptides and lipid membranes, whereas the latter are antibiotics whose pore-forming capacities are of great interest to act as target-specific drug candidates. From the molecular dynamics simulations of the WALP-peptides it is shown that the apparent hydrophobic mismatch between peptide and membrane can be resolved by two mechanisms (membrane thickness adaptation and peptide tilting) and that these two mechanisms occur sequential and not in parallel. In the case of the antimicrobial peptides it is shown that many of the orientations found with the molecular simulation techniques are in agreement with experimental observations. The second case to show the applicability of the molecular modeling techniques is that of the heat transfer characteristics of gas flows in nanochannels. Understanding these characteristics is important, because these very small channels are considered to be promising devices to locally cool systems (such as computer processing units) or to be used in lab-on-chip devices for at home medical diagnostics. Thus, understanding the interactions between the channel walls and the gas flow is of great importance. Unfortunately, the computational cost involved in simulating the solid wall, currently restrains the size of the systems that can be investigated using molecular dynamics simulations. Therefore, instead of the explicit modeling of the solid wall, appropriate boundary conditions are used, such as wall potentials or stochastic models. Both of these boundary conditions are examined in great detail and a new wall potential is presented. Also the investigations of a specific case of a channel with platinum walls with a noble gas (argon or xenon) in between allows to introduce a new method to compute an important heat transfer determining parameter. Furthermore, it is shown that both boundary conditions have their benefits and drawbacks, and that the use of either one depends heavily on the application under consideration. Both cases used to show the applicability of molecular modeling techniques, although very different from each other, indicate the importance of particle simulation methods. Investigating the interactions at the molecular level, and the development of new models allows for an even better understanding of underlying molecular processes

Water-induced correlation between single ions imaged at the solid–liquid interface

When immersed into ​water, most solids develop a surface charge, which is neutralized by an accumulation of dissolved counterions at the interface. Although the density distribution of counterions perpendicular to the interface obeys well-established theories, little is known about counterions’ lateral organization at the surface of the solid. Here we show, by using atomic force microscopy and computer simulations, that single hydrated metal ions can spontaneously form ordered structures at the surface of homogeneous solids in aqueous solutions. The structures are laterally stabilized only by ​water molecules with no need for specific interactions between the surface and the ions. The mechanism, studied here for several systems, is controlled by the hydration landscape of both the surface and the adsorbed ions. The existence of discrete ion domains could play an important role in interfacial phenomena such as charge transfer, crystal growth, nanoscale self-assembly and colloidal stability

Molecular dynamics study of vesicle deformation mechanisms

Lipid bilayer membranes are known to form various structures like large sheets or vesicles. When both bilayer leaflets have equal composition, membranes preferentially form flat sheets or spherical vesicles. However, vesicles with a wide variety of shapes, including ellipsoids, discoids, pear-shaped, cup-shaped and budded vesicles, have been shown experimentally. Such shapes were predicted theoretically from energy minimization of continuous sheets as well. We show, using coarse-grained molecular dynamics simulations, how relatively small asymmetry in composition between the two leaflets may result in spontaneously curved bilayers and all these vesicle shapes. Three types of bilayer asymmetry are considered. Firstly, the situation where the headgroup-solvent interaction and thus the lipid packing alters due to a change in pH or ion-concentration of the vesicle interior/exterior (A). Secondly, where asymmetry arises from phase separation of two lipid types (B). And thirdly, where asymmetry arises from growth of one of the bilayer leaflets by incorporation of additional lipids from the solvent (C)

Coarse Grained Molecular Dynamics Simulations of the Fusion of Vesicles Incorporating Water Channels

As the dynamics of the cell membrane and the working mechanisms of proteins cannot be readily asserted at a molecular level, many different hypotheses exist that try to predict and explain these processes, for instance vesicle fusion. Therefore, we use coarse grained molecular dynamics simulations to elucidate the fusion mechanism of vesicles. The implementation of this method with hydrophilic and hydrophobic particles is known for its valid representation of bilayers. With a minimalistic approach, using only 3 atom types, 12 atoms per two-tailed phospholipids and incorporating only a bond potential and Lennard-Jones potential, phospholipid bilayers and vesicles can be simulated exhibiting authentic dynamics. We have simulated the spontaneous full fusion of both tiny (6 nm diameter) and larger (13 nm diameter) vesicles. We showed that, without applying constraints to the vesicles, the initial contact between two fusing vesicles, the stalk, is initiated by a bridging lipid tail that extends from the membrane spontaneously. Subsequently it is observed that the evolution of the stalk can proceed via two pathways, anisotropic and radial expansion, which is in accordance with literature. Contrary to the spherical vesicles of in vitro experiments, the fused vesicles remain tubular since the internal volume of these vesicles is too small compared to their membrane area. While the lipid bilayer has some permeability for water, it is not high enough to allow for the large flux required to equilibrate the vesicle content in the time accessible to our simulations. To increase the membrane permeability, we incorporate proteinaceous water channels, by applying the coarse grained technique to aquaporin. Even though incorporating water channels in the vesicles does significantly increase water permeability, the vesicles do not become spherical. Presumably the lipids have to be redistributed as well

Mechanism of atomic force microscopy imaging of three-dimensional hydration structures at a solid-liquid interface

Here we present both subnanometer imaging of three-dimensional (3D) hydration structures using atomic force microscopy (AFM) and molecular dynamics simulations of the calcite-water interface. In AFM, by scanning the 3D interfacial space in pure water and recording the force on the tip, a 3D force image can be produced, which can then be directly compared to the simulated 3D water density and forces on a model tip. Analyzing in depth the resemblance between experiment and simulation as a function of the tip-sample distance allowed us to clarify the contrast mechanism in the force images and the reason for their agreement with water density distributions. This work aims to form the theoretical basis for AFM imaging of hydration structures and enables its application to future studies on important interfacial processes at the molecular scale

Search filters to identify geriatric medicine in Medline

Objectives To create user-friendly search filters with high sensitivity, specificity, and precision to identify articles on geriatric medicine in Medline. Design A diagnostic test assessment framework was used. A reference set of 2255 articles was created by hand-searching 22 biomedical journals in Medline, and each article was labeled as 'relevant', 'not relevant', or 'possibly relevant' for geriatric medicine. From the relevant articles, search terms were identified to compile different search strategies. The articles retrieved by the various search strategies were compared with articles from the reference set as the index test to create the search filters. Measures Sensitivity, specificity, precision, accuracy, and number-needed-to-read (NNR) were calculated by comparing the results retrieved by the different search strategies with the reference set. Results The most sensitive search filter had a sensitivity of 94.8%, a specificity of 88.7%, a precision of 73.0%, and an accuracy of 90.2%. It had an NNR of 1.37. The most specific search filter had a specificity of 96.6%, a sensitivity of 69.1%, a precision of 86.6%, and an accuracy of 89.9%. It had an NNR of 1.15. Conclusion These geriatric search filters simplify searching for relevant literature and therefore contribute to better evidence-based practice. The filters are useful to both the clinician who wants to find a quick answer to a clinical question and the researcher who wants to find as many relevant articles as possible without retrieving too many irrelevant article

National land use specific reference values: a basis for maximum values in Dutch soil policy

The National Institute for Public Health and the Environment has derived Reference Values for maximum permissible soil pollution. The Netherlands Ministry of Housing, Spatial Planning and the Environment (VROM) used these values as a basis for the maximum values for soil pollution. The ministry set these values down according to a proposal for an update of soil policy and the Soil Protection Act in 2003. Reference values refer to allowed concentrations of pollutants in soil, depending on the land use. The soil concentrations of pollutants with values below these concentrations meet all the requirements. The risks for humans, the ecosystem and agriculture were analyzed as critical factors, with risk thresholds derived for different types of land use, such as playgrounds, gardens, and agricultural and nature areas. Furthermore, an accelerated procedure was used to compile a complete list of reference values in 2006. The RIVM used state-of-the-art knowledge to complete the 'old' knowledge for information on toxicity of substances; figures were used where knowledge gaps occurred. A recommendation for the coming years is to address resulting inconsistencies in the list of reference values.Het RIVM heeft de referentiewaarden afgeleid waarmee het ministerie van VROM de maximaal toelaatbare bodemverontreinigingen onderbouwt (maximale waarden). Het ministerie heeft deze normen ingesteld in lijn met zijn voorstel uit 2003 om het bodembeleid en de Wet bodembescherming te actualiseren. Referentiewaarden zijn concentraties van verontreinigende stoffen in de bodem die, afhankelijk van het bodemgebruik, zijn toegestaan. Onder deze concentraties voldoet de bodem aan alle eisen. Voor verschillende vormen van bodemgebruik, zoals landbouw, kinderspeelplaatsen of industrie, zijn grensgehalten voor risico's bepaald. Dat zijn bijvoorbeeld, afhankelijk van het gebruik, risico's voor de mens, voor het ecosysteem en voor de landbouw. Het RIVM heeft gebruikgemaakt van een versnelde procedure om in 2006 een compleet voorstel van referentiewaarden gereed te hebben. Die snelheid was ingegeven door de werkgroep NOBO (normstelling en bodemkwaliteitsbeoordeling). Deze werkgroep heeft tevens uitgangspunten en beslissingen geformuleerd op basis waarvan het RIVM de referentiewaarden heeft afgeleid. Het RIVM heeft voor zijn onderzoek zo veel mogelijk gebruikgemaakt van de nieuwste kennis en inzichten, voor zover die beschikbaar zijn. Deze informatie is aangevuld met 'oude' kennis over stoffen. Deze combinatie heeft evenwel tot inconsistenties geleid in de afleiding van referentiewaarden. Het RIVM beveelt daarom aan de komende jaren aandacht te besteden aan de inconsistenties en zwakke plekken van de referentiewaarden

Cost-effectiveness of twice-weekly versus once-weekly sessions of cognitive-behavioural therapy and interpersonal psychotherapy for depression at 12 months after start of treatment : randomised controlled trial

BACKGROUND: Cost-effective treatments are needed to reduce the burden of depression. One way to improve the cost-effectiveness of psychotherapy might be to increase session frequency, but keep the total number of sessions constant. AIM: To evaluate the cost-effectiveness of twice-weekly compared with once-weekly psychotherapy sessions after 12 months, from a societal perspective. METHOD: An economic evaluation was conducted alongside a randomised controlled trial comparing twice-weekly versus once-weekly sessions of psychotherapy (cognitive-behavioural therapy or interpersonal psychotherapy) for depression. Missing data were handled by multiple imputation. Statistical uncertainty was estimated with bootstrapping and presented with cost-effectiveness acceptability curves. RESULTS: Differences between the two groups in depressive symptoms, physical and social functioning, and quality-adjusted life-years (QALY) at 12-month follow-up were small and not statistically significant. Total societal costs in the twice-weekly session group were higher, albeit not statistically significantly so, than in the once-weekly session group (mean difference €2065, 95% CI -686 to 5146). The probability that twice-weekly sessions are cost-effective compared with once-weekly sessions was 0.40 at a ceiling ratio of €1000 per point improvement in Beck Depression Inventory-II score, 0.32 at a ceiling ratio of €50 000 per QALY gained, 0.23 at a ceiling ratio of €1000 per point improvement in physical functioning score and 0.62 at a ceiling ratio of €1000 per point improvement in social functioning score. CONCLUSIONS: Based on the current results, twice-weekly sessions of psychotherapy for depression are not cost-effective over the long term compared with once-weekly sessions