The 2',4'-dihydroxychalcone could be explored to develop new inhibitors against the glycerol-3-phosphate dehydrogenase from Leishmania species

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Um novo protocolo in silico para a predição de complexos flexíveis entre proteínas: estudo de caso para inibidores plasmáticos de fosfolipase A2 de serpentes

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Hb S-Sao Paulo: A new sickling hemoglobin with stable polymers and decreased oxygen affinity

Hb S-Sao Paulo (SP) [HBB:c.20A > T p.Glu6Val: c.196A > G p.Lys65Glu] is a new double-mutant hemoglobin that was found in heterozygosis in an 18-month-old Brazilian male with moderate anemia. It behaves like Hb S in acid electrophoresis, isoelectric focusing and solubility testing but shows different behavior in alkaline electrophoresis, cation-exchange HPLC and RP-HPLC. The variant is slightly unstable, showed reduced oxygen affinity and also appeared to form polymers more stable than the Hb S. Molecular dynamics simulation suggests that the polymerization is favored by interfacial electrostatic interactions. This provides a plausible explanation for some of the reported experimental observations. (C) 2012 Elsevier Inc. All rights reserved.

Conformation analysis of a surface loop that controls active site access in the GH11 xylanase A from Bacillus subtilis

Xylanases (EC 3.2.1.8 endo-1,4-glycosyl hydrolase) catalyze the hydrolysis of xylan, an abundant hemicellulose of plant cell walls. Access to the catalytic site of GH11 xylanases is regulated by movement of a short beta-hairpin, the so-called thumb region, which can adopt open or closed conformations. A crystallographic study has shown that the D11F/R122D mutant of the GH11 xylanase A from Bacillus subtilis (BsXA) displays a stable "open" conformation, and here we report a molecular dynamics simulation study comparing this mutant with the native enzyme over a range of temperatures. The mutant open conformation was stable at 300 and 328 K, however it showed a transition to the closed state at 338 K. Analysis of dihedral angles identified thumb region residues Y113 and T123 as key hinge points which determine the open-closed transition at 338 K. Although the D11F/R122D mutations result in a reduction in local inter-intramolecular hydrogen bonding, the global energies of the open and closed conformations in the native enzyme are equivalent, suggesting that the two conformations are equally accessible. These results indicate that the thumb region shows a broader degree of energetically permissible conformations which regulate the access to the active site region. The R122D mutation contributes to the stability of the open conformation, but is not essential for thumb dynamics, i.e., the wild type enzyme can also adapt to the open conformation.

The Equilibrium Structure of Lithium Salt Solutions in Ether-Functionalized Ammonium Ionic Liquids

Molecular dynamics simulations have been performed for ionic liquids based on a ternary mixture of lithium and ammonium cations and a common anion, bis(trifluoromethylsulfonyl)imide, [Tf2N](-). We address structural changes resulting from adding Li+ in ionic liquids with increasing length of an ether-functionalized chain in the ammonium cation. The calculation of static structure factors reveals the lithium effect on charge ordering and intermediate range order in comparison with the neat ionic liquids. The charge ordering is modified in the lithium solution because the coordination of [Tf2N](-) toward Li+ is much stronger than ammonium cations. Intermediate range order is observed in neat ionic liquids based on ammonium cations with a long chain, but in the lithium solutions, there is also a nonhomogenous distribution of Li+ cations. The presence of Li+ enhances interactions between the ammonium cations due to correlations between the oxygen atom of the ether chain and the nitrogen atom of another ammonium cation.

Theoretical studies of microfluidics: "walking" drops and "melting" snowflakes.

The present PhD thesis summarizes two examples of research in microfluidics. Both times water was the subject of interest, once in the liquid state (droplets adsorbed on chemically functionalized surfaces), the other time in the solid state (ice snowflakes and their fractal behaviour). The first problem deals with a slipping nano-droplet of water adsorbed on a surface with photo-switchable wettability characteristics. Main focus was on identifying the underlying driving forces and mechanical principles at the molecular level of detail. Molecular Dynamics simulation was employed as investigative tool owing to its record of successfully describing the microscopic behaviour of liquids at interfaces. To reproduce the specialized surface on which a water droplet can effectively “walk”, a new implicit surface potential was developed. Applying this new method the experimentally observed droplet slippage could be reproduced successfully. Next the movement of the droplet was analyzed at various conditions emphasizing on the behaviour of the water molecules in contact with the surface. The main objective was to identify driving forces and molecular mechanisms underlying the slippage process. The second part of this thesis is concerned with theoretical studies of snowflake melting. In the present work snowflakes are represented by filled von Koch-like fractals of mesoscopic beads. A new algorithm has been developed from scratch to simulate the thermal collapse of fractal structures based on Monte Carlo and Random Walk Simulations (MCRWS). The developed method was applied and compared to Molecular Dynamics simulations regarding the melting of ice snowflake crystals and new parameters were derived from this comparison. Bigger snow-fractals were then studied looking at the time evolution at different temperatures again making use of the developed MCRWS method. This was accompanied by an in-depth analysis of fractal properties (border length and gyration radius) in order to shed light on the dynamics of the melting process.

Thermodynamic concepts in adaptive resolution simulations

This thesis work is devoted to the conceptual and technical development of the Adaptive Resolution Scheme (AdResS), a molecular dynamics method that allows the simulation of a system with different levels of resolution simultaneously. The simulation domain is divided into high and low resolution zones and a transition region that links them, through which molecules can freely diffuse.rnThe first issue of this work regards the thermodynamic consistency of the method, which is tested and verified in a model liquid of tetrahedral molecules. The results allow the introduction of the concept of the Thermodynamic Force, an external field able to correct spurious density fluctuations present in the transition region in usual AdResS simulations.rnThe AdResS is also applied to a system where two different representations with the same degree of resolution are confronted. This simple test extends the method from an Adaptive Resolution Scheme to an Adaptive Representation Scheme, providing a way of coupling different force fields based on thermodynamic consistency arguments. The Thermodynamic Force is successfully applied to the example described in this work as well.rnAn alternative approach of deducing the Thermodynamic Force from pressure consistency considerations allows the interpretation of AdResS as a first step towards a molecular dynamics simulation in the Grand Canonical ensemble. Additionally, such a definition leads to a practical way of determining the Thermodynamic Force, tested in the well studied tetrahedral liquid. The effects of AdResS and this correction on the atomistic domain are analyzed by inspecting the local distribution of velocities, radial distribution functions, pressure and particle number fluctuation. Their comparison with analogous results coming from purely atomistic simulations shows good agreement, which is greatly improved under the effect of the external field.rnA further step in the development of AdResS, necessary for several applications in biophysics and material science, consists of its application to multicomponent systems. To this aim, the high-resolution representation of a model binary mixture is confronted with its coarse-grained representation systematically parametrized. The Thermodynamic Force, whose development requires a more delicate treatment, also gives satisfactory results.rnFinally, AdResS is tested in systems including two-body bonded forces, through the simulation of a model polymer allowed to adaptively change its representation. It is shown that the distribution functions that characterize the polymer structure are in practice not affected by the change of resolution.rnThe technical details of the implementation of AdResS in the ESPResSo package conclude this thesis work.

Ab-initio study of hydrogen technology materials for hydrogen storage and proton conduction

This dissertation deals with two specific aspects of a potential hydrogen-based energy economy, namely the problems of energy storage and energy conversion. In order to contribute to the solution of these problems, the structural and dynamical properties of two promising materials for hydrogen storage (lithium imide/amide) and proton conduction (poly[vinyl phosphonic acid]) are modeled on an atomistic scale by means of first principles molecular dynamics simulation methods.rnrnrnIn the case of the hydrogen storage system lithium amide/imide (LiNH_2/Li_2NH), the focus was on the interplay of structural features and nuclear quantum effects. For these calculations, Path-Integral Molecular Dynamics (PIMD) simulations were used. The structures of these materials at room temperature were elucidated; in collaboration with an experimental group, a very good agreement between calculated and experimental solid-state 1H-NMR chemical shifts was observed. Specifically, the structure of Li_2NH features a disordered arrangement of the Li lattice, which was not reported in previous studies. In addition, a persistent precession of the NH bonds was observed in our simulations. We provide evidence that this precession is the consequence of a toroid-shaped effective potential, in which the protons in the material are immersed. This potential is essentially flat along the torus azimuthal angle, which might lead to important quantum delocalization effects of the protons over the torus.rnrnOn the energy conversion side, the dynamics of protons in a proton conducting polymer (poly[vinyl phosphonic acid], PVPA) was studied by means of a steered ab-initio Molecular Dynamics approach applied on a simplified polymer model. The focus was put on understanding the microscopic proton transport mechanism in polymer membranes, and on characterizing the relevance of the local environment. This covers particularly the effect of water molecules, which participate in the hydrogen bonding network in the material. The results indicate that these water molecules are essential for the effectiveness of proton conduction. A water-mediated Grotthuss mechanism is identified as the main contributor to proton conduction, which agrees with the experimentally observed decay on conductivity for the same material in the absence of water molecules.rnrnThe gain in understanding the microscopic processes and structures present in this materials can help the development of new materials with improved properties, thus contributing to the solution of problems in the implementation of fuel cells.

Computational Study of the Fe(CN)(2)CO Cofactor and Its Binding to HypC Protein.

In the intricate maturation process of [NiFe]-hydrogenases, the Fe(CN)2CO cofactor is first assembled in a HypCD complex with iron coordinated by cysteines from both proteins and CO is added after ligation of cyanides. The small accessory protein HypC is known to play a role in delivering the cofactor needed for assembling the hydrogenase active site. However, the chemical nature of the Fe(CN)2CO moiety and the stability of the cofactor–HypC complex are open questions. In this work, we address geometries, properties, and the nature of bonding of all chemical species involved in formation and binding of the cofactor by means of quantum calculations. We also study the influence of environmental effects and binding to cysteines on vibrational frequencies of stretching modes of CO and CN used to detect the presence of Fe(CN)2CO. Carbon monoxide is found to be much more sensitive to sulfur binding and the polarity of the medium than cyanides. The stability of the HypC–cofactor complex is analyzed by means of molecular dynamics simulation of cofactor-free and cofactor-bound forms of HypC. The results show that HypC is stable enough to carry the cofactor, but since its binding cysteine is located at the N-terminal unstructured tail, it presents large motions in solution, which suggests the need for a guiding interaction to achieve delivery of the cofactor.

Dynamical hierarchy in transition states: Why and how does a system climb over the mountain?

How a reacting system climbs through a transition state during the course of a reaction has been an intriguing subject for decades. Here we present and quantify a technique to identify and characterize local invariances about the transition state of an N-particle Hamiltonian system, using Lie canonical perturbation theory combined with microcanonical molecular dynamics simulation. We show that at least three distinct energy regimes of dynamical behavior occur in the region of the transition state, distinguished by the extent of their local dynamical invariance and regularity. Isomerization of a six-atom Lennard–Jones cluster illustrates this: up to energies high enough to make the system manifestly chaotic, approximate invariants of motion associated with a reaction coordinate in phase space imply a many-body dividing hypersurface in phase space that is free of recrossings even in a sea of chaos. The method makes it possible to visualize the stable and unstable invariant manifolds leading to and from the transition state, i.e., the reaction path in phase space, and how this regularity turns to chaos with increasing total energy of the system. This, in turn, illuminates a new type of phase space bottleneck in the region of a transition state that emerges as the total energy and mode coupling increase, which keeps a reacting system increasingly trapped in that region.

Comparisons of diffusive and viscous contributions to transport coefficients of light gases in single-walled carbon nanotubes

We examine here the relative importance of different contributions to transport of light gases in single walled carbon nanotubes, using methane and hydrogen as examples. Transport coefficients at 298 K are determined using molecular dynamics simulation with atomistic models of the nanotube wall, from which the diffusive and viscous contributions are resolved using a recent approach that provides an explicit expression for the latter. We also exploit an exact theory for the transport of Lennard-Jones fluids at low density considering diffuse reflection at the tube wall, thereby permitting the estimation of Maxwell coefficients for the wall reflection. It is found that reflection from the carbon nanotube wall is nearly specular, as a result of which slip flow dominates, and the viscous contribution is small in comparison, even for a tube as large as 8.1 nm in diameter. The reflection coefficient for hydrogen is 3-6 times as large as that for methane in tubes of 1.36 nm diameter, indicating less specular reflection for hydrogen and greater sensitivity to atomic detail of the surface. This reconciles results showing that transport coefficients for hydrogen and methane, obtained in simulation, are comparable in tubes of this size. With increase in adsorbate density, the reflection coefficient increases, suggesting that adsorbate interactions near the wall serve to roughen the local potential energy landscape perceived by fluid molecules.

Interfacial interactions and structure of polyurethane intercalated nanocomposite

Understanding the interfacial interactions between the nanofiller and polymer matrix is important to improve the design and manufacture of polymer nanocomposites. This paper reports a molecular dynamic Study on the interfacial interactions and structure of a clay-based polyurethane intercalated nanocomposite. The results show that the intercalation of surfactant (i.e. dioctadecyldlmethyl ammonium) and polyurethane (PU) into the nanoconfined gallery of clay leads to the multilayer structure for both surfactant and PU, and the absence of phase separation for PU chains. Such structural characteristics are attributed to the result of competitive interactions among the surfactant, PU and the clay surface, including van der Waals, electrostatic and hydrogen bonding.

Quantum effects on adsorption and diffusion of hydrogen and deuterium in microporous materials

Monte Carlo and molecular dynamics simulations and neutron scattering experiments are used to study the adsorption and diffusion of hydrogen and deuterium in zeolite Rho in the temperature range of 30-150 K. In the molecular simulations, quantum effects are incorporated via the Feynman-Hibbs variational approach. We suggest a new set of potential parameters for hydrogen, which can be used when Feynman-Hibbs variational approach is used for quantum corrections. The dynamic properties obtained from molecular dynamics simulations are in excellent agreement with the experimental results and show significant quantum effects on the transport at very low temperature. The molecular dynamics simulation results show that the quantum effect is very sensitive to pore dimensions and under suitable conditions can lead to a reverse kinetic molecular sieving with deuterium diffusing faster than hydrogen.

The effect of box shape on the dynamic properties of proteins simulated under periodic boundary conditions

The effect of the box shape on the dynamic behavior of proteins simulated under periodic boundary conditions is evaluated. In particular, the influence of simulation boxes defined by the near-densest lattice packing (NDLP) in conjunction with rotational constraints is compared to that of standard box types without these constraints. Three different proteins of varying size, shape, and secondary structure content were examined in the study. The statistical significance of differences in RMSD, radius of gyration, solvent-accessible surface, number of hydrogen bonds, and secondary structure content between proteins, box types, and the application or not of rotational constraints has been assessed. Furthermore, the differences in the collective modes for each protein between different boxes and the application or not of rotational constraints have been examined. In total 105 simulations were performed, and the results compared using a three-way multivariate analysis of variance (MANOVA) for properties derived from the trajectories and a three-way univariate analysis of variance (ANOVA) for collective modes. It is shown that application of roto-translational constraints does not have a statistically significant effect on the results obtained from the different simulations. However, the choice of simulation box was found to have a small (5-10%), but statistically significant effect on the behavior of two of the three proteins included in the study. (c) 2005 Wiley Periodicals, Inc.

An Adaptation of the Hoshen-Kopelman Cluster Counting Algorithm for Honeycomb Networks

We develop a simplified implementation of the Hoshen-Kopelman cluster counting algorithm adapted for honeycomb networks. In our implementation of the algorithm we assume that all nodes in the network are occupied and links between nodes can be intact or broken. The algorithm counts how many clusters there are in the network and determines which nodes belong to each cluster. The network information is stored into two sets of data. The first one is related to the connectivity of the nodes and the second one to the state of links. The algorithm finds all clusters in only one scan across the network and thereafter cluster relabeling operates on a vector whose size is much smaller than the size of the network. Counting the number of clusters of each size, the algorithm determines the cluster size probability distribution from which the mean cluster size parameter can be estimated. Although our implementation of the Hoshen-Kopelman algorithm works only for networks with a honeycomb (hexagonal) structure, it can be easily changed to be applied for networks with arbitrary connectivity between the nodes (triangular, square, etc.). The proposed adaptation of the Hoshen-Kopelman cluster counting algorithm is applied to studying the thermal degradation of a graphene-like honeycomb membrane by means of Molecular Dynamics simulation with a Langevin thermostat. ACM Computing Classification System (1998): F.2.2, I.5.3.