Distinct conformational properties determined by implicit and explicit representation of protein-solvent interactions. An analytical and computer simulation study

In the protein folding problem, solvent-mediated forces are commonly represented by intra-chain pairwise contact energy. Although this approximation has proven to be useful in several circumstances, it is limited in some other aspects of the problem. Here we show that it is possible to achieve two models to represent the chain-solvent system. one of them with implicit and other with explicit solvent, such that both reproduce the same thermodynamic results. Firstly, lattice models treated by analytical methods, were used to show that the implicit and explicitly representation of solvent effects can be energetically equivalent only if local solvent properties are time and spatially invariant. Following, applying the same reasoning Used for the lattice models, two inter-consistent Monte Carlo off-lattice models for implicit and explicit solvent are constructed, being that now in the latter the solvent properties are allowed to fluctuate. Then, it is shown that the chain configurational evolution as well as the globule equilibrium conformation are significantly distinct for implicit and explicit solvent systems. Actually, strongly contrasting with the implicit solvent version, the explicit solvent model predicts: (i) a malleable globule, in agreement with the estimated large protein-volume fluctuations; (ii) thermal conformational stability, resembling the conformational hear resistance of globular proteins, in which radii of gyration are practically insensitive to thermal effects over a relatively wide range of temperatures; and (iii) smaller radii of gyration at higher temperatures, indicating that the chain conformational entropy in the unfolded state is significantly smaller than that estimated from random coil configurations. Finally, we comment on the meaning of these results with respect to the understanding of the folding process. (C) 2009 Elsevier B.V. All rights reserved.

Transport coefficients, Raman spectroscopy, and computer simulation of lithium salt solutions in an ionic liquid

Lithium salt solutions of Li(CF3SO2)(2)N, LiTFSI, in a room-temperature ionic liquid (RTIL), 1-butyl-2,3-dimethyl-imidazolium cation, BMMI, and the (CF3SO2)(2)N-, bis(trifluoromethanesulfonyl)imide anion, [BMMI][TFSI], were prepared in different concentrations. Thermal properties, density, viscosity, ionic conductivity, and self-diffusion coefficients were determined at different temperatures for pure [BMMI][TFSI] and the lithium solutions. Raman spectroscopy measurements and computer simulations were also carried out in order to understand the microscopic origin of the observed changes in transport coefficients. Slopes of Walden plots for conductivity and fluidity, and the ratio between the actual conductivity and the Nernst-Einstein estimate for conductivity, decrease with increasing LiTFSI content. All of these studies indicated the formation of aggregates of different chemical nature, as it is corroborated by the Raman spectra. In addition, molecular dynamics (MD) simulations showed that the coordination of Li+ by oxygen atoms of TFSI anions changes with Li+ concentration producing a remarkable change of the RTIL structure with a concomitant reduction of diffusion coefficients of all species in the solutions.

Black-box decomposition approach for computational hemodynamics: One-dimensional models

Increasing efforts exist in integrating different levels of detail in models of the cardiovascular system. For instance, one-dimensional representations are employed to model the systemic circulation. In this context, effective and black-box-type decomposition strategies for one-dimensional networks are needed, so as to: (i) employ domain decomposition strategies for large systemic models (1D-1D coupling) and (ii) provide the conceptual basis for dimensionally-heterogeneous representations (1D-3D coupling, among various possibilities). The strategy proposed in this article works for both of these two scenarios, though the several applications shown to illustrate its performance focus on the 1D-1D coupling case. A one-dimensional network is decomposed in such a way that each coupling point connects two (and not more) of the sub-networks. At each of the M connection points two unknowns are defined: the flow rate and pressure. These 2M unknowns are determined by 2M equations, since each sub-network provides one (non-linear) equation per coupling point. It is shown how to build the 2M x 2M non-linear system with arbitrary and independent choice of boundary conditions for each of the sub-networks. The idea is then to solve this non-linear system until convergence, which guarantees strong coupling of the complete network. In other words, if the non-linear solver converges at each time step, the solution coincides with what would be obtained by monolithically modeling the whole network. The decomposition thus imposes no stability restriction on the choice of the time step size. Effective iterative strategies for the non-linear system that preserve the black-box character of the decomposition are then explored. Several variants of matrix-free Broyden`s and Newton-GMRES algorithms are assessed as numerical solvers by comparing their performance on sub-critical wave propagation problems which range from academic test cases to realistic cardiovascular applications. A specific variant of Broyden`s algorithm is identified and recommended on the basis of its computer cost and reliability. (C) 2010 Elsevier B.V. All rights reserved.

Resultados preliminares de um algoritmo para ablação de lente de contato personalizada

OBJETIVO: Desenvolver simulação computadorizada de ablação para produzir lentes de contato personalizadas a fim de corrigir aberrações de alta ordem. MÉTODOS: Usando dados reais de um paciente com ceratocone, mensurados em um aberrômetro ("wavefront") com sensor Hartmann-Shack, foram determinados as espessuras de lentes de contato que compensam essas aberrações assim como os números de pulsos necessários para fazer ablação as lentes especificamente para este paciente. RESULTADOS: Os mapas de correção são apresentados e os números dos pulsos foram calculados, usando feixes com a largura de 0,5 mm e profundidade de ablação de 0,3 µm. CONCLUSÕES: Os resultados simulados foram promissores, mas ainda precisam ser aprimorados para que o sistema de ablação "real" possa alcançar a precisão desejada.

AcMus: an open, integrated platform for room acoustics research

This article describes the design, implementation, and experiences with AcMus, an open and integrated software platform for room acoustics research, which comprises tools for measurement, analysis, and simulation of rooms for music listening and production. Through use of affordable hardware, such as laptops, consumer audio interfaces and microphones, the software allows evaluation of relevant acoustical parameters with stable and consistent results, thus providing valuable information in the diagnosis of acoustical problems, as well as the possibility of simulating modifications in the room through analytical models. The system is open-source and based on a flexible and extensible Java plug-in framework, allowing for cross-platform portability, accessibility and experimentation, thus fostering collaboration of users, developers and researchers in the field of room acoustics.

Polarization effects in molecular dynamics simulations of glass-formers Ca(NO(3))(2)center dot nH(2)O, n=4, 6, and 8

Thermodynamics, equilibrium structure, and dynamics of glass-forming liquids Ca(NO(3))(2)center dot nH(2)O, n=4, 6, and 8, have been investigated by molecular dynamics (MD) simulations. A polarizable model was considered for H(2)O and NO(3)- on the basis of previous fluctuating charge models for pure water and the molten salt 2Ca(NO(3))(2)center dot 3KNO(3). Similar thermodynamic properties have been obtained with nonpolarizable and polarizable models. The glass transition temperature, T(g), estimated from MD simulations was dependent on polarization, in particular the dependence of T(g) with electrolyte concentration. Significant polarization effects on equilibrium structure were observed in cation-cation, cation-anion, and water-water structures. Polarization increases the diffusion coefficient of H(2)O, but does not change significantly the diffusion coefficients of ions. Viscosity decreases upon inclusion of polarization, but the conductivity calculated with the polarizable model is smaller than the nonpolarizable model because polarization enhances anion-cation interactions.

Computer-Assisted Numerical Analysis for Oxygen and Carbon Dioxide Mass Transfer in Blood Oxygenators

A two-dimensional numeric simulator is developed to predict the nonlinear, convective-reactive, oxygen mass exchange in a cross-flow hollow fiber blood oxygenator. The numeric simulator also calculates the carbon dioxide mass exchange, as hemoglobin affinity to oxygen is affected by the local pH value, which depends mostly on the local carbon dioxide content in blood. Blood pH calculation inside the oxygenator is made by the simultaneous solution of an equation that takes into account the blood buffering capacity and the classical Henderson-Hasselbach equation. The modeling of the mass transfer conductance in the blood comprises a global factor, which is a function of the Reynolds number, and a local factor, which takes into account the amount of oxygen reacted to hemoglobin. The simulator is calibrated against experimental data for an in-line fiber bundle. The results are: (i) the calibration process allows the precise determination of the mass transfer conductance for both oxygen and carbon dioxide; (ii) very alkaline pH values occur in the blood path at the gas inlet side of the fiber bundle; (iii) the parametric analysis of the effect of the blood base excess (BE) shows that V(CO2) is similar in the case of blood metabolic alkalosis, metabolic acidosis, or normal BE, for a similar blood inlet P(CO2), although the condition of metabolic alkalosis is the worst case, as the pH in the vicinity of the gas inlet is the most alkaline; (iv) the parametric analysis of the effect of the gas flow to blood flow ratio (Q(G)/Q(B)) shows that V(CO2) variation with the gas flow is almost linear up to Q(G)/Q(B) = 2.0. V(O2) is not affected by the gas flow as it was observed that by increasing the gas flow up to eight times, the V(O2) grows only 1%. The mass exchange of carbon dioxide uses the full length of the hollow-fiber only if Q(G)/Q(B) > 2.0, as it was observed that only in this condition does the local variation of pH and blood P(CO2) comprise the whole fiber bundle.

Log-modified Weibull regression models with censored data: Sensitivity and residual analysis

This paper proposes a regression model considering the modified Weibull distribution. This distribution can be used to model bathtub-shaped failure rate functions. Assuming censored data, we consider maximum likelihood and Jackknife estimators for the parameters of the model. We derive the appropriate matrices for assessing local influence on the parameter estimates under different perturbation schemes and we also present some ways to perform global influence. Besides, for different parameter settings, sample sizes and censoring percentages, various simulations are performed and the empirical distribution of the modified deviance residual is displayed and compared with the standard normal distribution. These studies suggest that the residual analysis usually performed in normal linear regression models can be straightforwardly extended for a martingale-type residual in log-modified Weibull regression models with censored data. Finally, we analyze a real data set under log-modified Weibull regression models. A diagnostic analysis and a model checking based on the modified deviance residual are performed to select appropriate models. (c) 2008 Elsevier B.V. All rights reserved.

Canine population dynamics: the potential effect of sterilization campaigns

Objective. To analyze, through mathematical modeling, the potential ability of sterilization campaigns to reduce the population density of pet dogs. Methods. Mathematical models were constructed to simulate the canine population dynamics and project the results of control strategies based on several sterilization rates. Results. Even at high sterilization rates (for example, 0.80 year(-1)), it would take approximately 5 years to reduce density by 20%. Even so, other sources of population growth, such as the importing of dogs from other geographic areas, could outweigh the effects of a sterilization program. Conclusions. A program`s effectiveness is contingent upon not only on the sterilization rate, but also the rate of population growth. Sterilization campaigns may potentially reduce population density, but this reduction may not be immediately evident.

Solvent Effects in Chemical Processes. Water-Assisted Proton Transfer Reaction of Pterin in Aqueous Environment

Pterins are members of a family of heterocyclic compounds present in a wide variety of biological systems and may exist in two forms, corresponding to an acid and a basic tautomer. In this work, the proton transfer reaction between these tautomeric forms was investigated in the gas phase and in aqueous solution. In gas phase, the intramolecular mechanism was carried out for die isolated pterin by quantum mechanical second-order Moller-Plesset Perturbation theory (MP2/aug-cc-pVDZ) calculations and it indicates that the acid form is more stable than the basic form by -1.4 kcal/mol with a barrier of 34.2 kcal/mol with respect to the basic form. In aqueous solution, the role of the water molecules in the proton transfer reaction was analyzed in two separated parts, the direct participation of one water molecule in the reaction path, called water-assisted mechanism, and the complementary participation of the aqueous solvation. The water-assisted mechanism was carried out for one pterin-water cluster by quantum mechanical calculations and it indicates that the acid form is still more stable by -3.3 kcal/mol with a drastic reduction of 70% of the barrier, The bulk solution effect on the intramolecular and water-assisted mechanisms was included by free energy perturbation implemented on Monte Carlo simulations. The bulk water effect is found to be substantial and decisive when the reaction path involves the water-assisted mechanism. In this case, the free energy barrier is only 6.7 kcal/mol and the calculated relative Gibbs free energy for the two tautomers is -11.2 kcal/mol. This value is used to calculate the pK(a) value of 8.2 +/- 0.6 that is in excellent agreement with the experimental result of 7.9.

Polarization and solvatochromic shift of ortho-betaine in water

Betaine dyes are known to show very large transition energy shifts in different solvents. The ortho-betaine molecule - a simple two-ring prototype of the E-T(30) Reichardt dye - has been investigated theoretically from a combined statistical and quantum mechanics approach. Using sequential Monte Carlo (MC) simulations and MP2/cc-pVDZ calculations the in-water dipole moment of ortho-betaine is obtained as 12.30 +/- 0.05 D. This result shows a considerable increase of 75% compared to the in-vacuum dipole moment. For comparison, the use of a polarizable continuum model using the same MP2/cc-pVDZ leads to an in-water dipole moment of 11.6 D, in good agreement. This large polarization is incorporated in the classical potential for another MC simulation to generate solute-solvent configurations and to obtain the contribution of the polarization effect in the solvatochromic shift. Using statistically uncorrelated configurations and supermolecular INDO/CIS calculations, including the solute and, explicitly, 230 solvent water molecules, the statistically converged calculated shift is obtained here as 6360 cm(-1), in good agreement with the experimental result of 7550 cm(-1). (c) 2007 Elsevier B.V. All rights reserved.

Improved likelihood inference in beta regression

We consider the issue of performing accurate small-sample likelihood-based inference in beta regression models, which are useful for modelling continuous proportions that are affected by independent variables. We derive small-sample adjustments to the likelihood ratio statistic in this class of models. The adjusted statistics can be easily implemented from standard statistical software. We present Monte Carlo simulations showing that inference based on the adjusted statistics we propose is much more reliable than that based on the usual likelihood ratio statistic. A real data example is presented.

Flexibility and inhibitor binding in Cdc25 phosphatases

Cdc25 phosphatases involved in cell cycle checkpoints are now active targets for the development of anti-cancer therapies. Rational drug design would certainly benefit from detailed structural information for Cdc25s. However, only apo- or sulfate-bound crystal structures of the Cdc25 catalytic domain have been described so far. Together with previously available crystalographic data, results from molecular dynamics simulations, bioinformatic analysis, and computer-generated conformational ensembles shown here indicate that the last 30-40 residues in the C-terminus of Cdc25B are partially unfolded or disordered in solution. The effect of C-terminal flexibility upon binding of two potent small molecule inhibitors to Cdc25B is then analyzed by using three structural models with variable levels of flexibility, including an equilibrium distributed ensemble of Cdc25B backbone conformations. The three Cdc25B structural models are used in combination with flexible docking, clustering, and calculation of binding free energies by the linear interaction energy approximation to construct and validate Cdc25B-inhibitor complexes. Two binding sites are identified on top and beside the Cdc25B active site. The diversity of interaction modes found increases with receptor flexibility. Backbone flexibility allows the formation of transient cavities or compact hydrophobic units on the surface of the stable, folded protein core that are unexposed or unavailable for ligand binding in rigid and densely packed crystal structures. The present results may help to speculate on the mechanisms of small molecule complexation to partially unfolded or locally disordered proteins.

Effect of SO(2) on the Transport Properties of an Imidazolium Ionic Liquid and Its Lithium Solution

Transport coefficients have been measured as a function of the concentration of sulfur dioxide, SO(2), dissolved in 1-butyl-2,3-dimethylimidazolium bis(trifluoromethylsulfonyl)-imide, [BMMI][Tf(2)N], as well as in its lithium salt solution, Li[Tf(2)N]. The SO(2) reduces viscosity and density and increases conductivity and diffusion coefficients in both the neat [BMMI] [Tf(2)N] and the [BMMI][Tf(2)N]-Li[Tf(2)N] solution. The conductivity enhancement is not assigned to a simple viscosity effect; the weakening of ionic interactions upon SO(2) addition also plays a role. Microscopic details of the SO(2) effect were unraveled using Raman spectroscopy and molecular dynamics (MD) simulations. The Raman spectra suggest that the Li(+)-[Tf(2)N] interaction is barely affected by SO(2), and the SO(2)-[Tf(2)N] interaction is weaker than previously observed in an investigation of an ionic liquid containing the bromide anion. Transport coefficients calculated by MD simulations show the same trend as the experimental data with respect to SO(2) content. The MD simulations provide structural information on SO(2) molecules around [Tf(2)N], in particular the interaction of the sulfur atom of SO(2) with oxygen and fluorine atoms of the anion. The SO(2)-[BMMI] interaction is also important because the [BMMI] cations with above-average mobility have a larger number of nearest-neighbor SO(2) molecules.

Uma perspectiva computacional sobre catálise enzimática

Enzymes are extremely efficient catalysts. Here, part of the mechanisms proposed to explain this catalytic power will be compared to quantitative experimental results and computer simulations. Influence of the enzymatic environment over species along the reaction coordinate will be analysed. Concepts of transition state stabilisation and reactant destabilisation will be confronted. Divided site model and near-attack conformation hypotheses will also be discussed. Molecular interactions such as covalent catalysis, general acid-base catalysis, electrostatics, entropic effects, steric hindrance, quantum and dynamical effects will also be analysed as sources of catalysis. Reaction mechanisms, in particular that catalysed by protein tyrosine phosphatases, illustrate the concepts.