Structure and electronic properties of hydrated mesityl oxide: a sequential quantum mechanics/molecular mechanics approach

The hydration of mesityl oxide (MOx) was investigated through a sequential quantum mechanics/molecular mechanics approach. Emphasis was placed on the analysis of the role played by water in the MOx syn-anti equilibrium and the electronic absorption spectrum. Results for the structure of the MOx-water solution, free energy of solvation and polarization effects are also reported. Our main conclusion was that in gas-phase and in low-polarity solvents, the MOx exists dominantly in syn-form and in aqueous solution in anti-form. This conclusion was supported by Gibbs free energy calculations in gas phase and in-water by quantum mechanical calculations with polarizable continuum model and thermodynamic perturbation theory in Monte Carlo simulations using a polarized MOx model. The consideration of the in-water polarization of the MOx is very important to correctly describe the solute-solvent electrostatic interaction. Our best estimate for the shift of the pi-pi* transition energy of MOx, when it changes from gas-phase to water solvent, shows a red-shift of -2,520 +/- 90 cm(-1), which is only 110 cm(-1) (0.014 eV) below the experimental extrapolation of -2,410 +/- 90 cm(-1). This red-shift of around -2,500 cm(-1) can be divided in two distinct and opposite contributions. One contribution is related to the syn -> anti conformational change leading to a blue-shift of similar to 1,700 cm(-1). Other contribution is the solvent effect on the electronic structure of the MOx leading to a red-shift of around -4,200 cm(-1). Additionally, this red-shift caused by the solvent effect on the electronic structure can by composed by approximately 60 % due to the electrostatic bulk effect, 10 % due to the explicit inclusion of the hydrogen-bonded water molecules and 30 % due to the explicit inclusion of the nearest water molecules.

Effect of the thermostat in the molecular dynamics simulation on the folding of the model protein chignolin

Molecular dynamics simulations of the model protein chignolin with explicit solvent were carried out, in order to analyze the influence of the Berendsen thermostat on the evolution and folding of the peptide. The dependence of the peptide behavior on temperature was tested with the commonly employed thermostat scheme consisting of one thermostat for the protein and another for the solvent. The thermostat coupling time of the protein was increased to infinity, when the protein is not in direct contact with the thermal bath, a situation known as minimally invasive thermostat. In agreement with other works, it was observed that only in the last situation the instantaneous temperature of the model protein obeys a canonical distribution. As for the folding studies, it was shown that, in the applications of the commonly utilized thermostat schemes, the systems are trapped in local minima regions from which it has difficulty escaping. With the minimally invasive thermostat the time that the protein needs to fold was reduced by two to three times. These results show that the obstacles to the evolution of the extended peptide to the folded structure can be overcome when the temperature of the peptide is not directly controlled.

Characterization of suramin binding sites on the human group IIA secreted phospholipase A(2) by site-directed mutagenesis and molecular dynamics simulation

Suramin is a polysulphonated naphthylurea with inhibitory activity against the human secreted group IIA phospholipase A(2) (hsPLA2GIIA), and we have investigated suramin binding to recombinant hsPLA2GIIA using site-directed mutagenesis and molecular dynamics (MD) simulations. The changes in suramin binding affinity of 13 cationic residue mutants of the hsPLA2GIIA was strongly correlated with alterations in the inhibition of membrane damaging activity of the protein. Suramin binding to hsPLA2GIIA was also studied by MD simulations, which demonstrated that altered intermolecular potential energy of the suramin/mutant complexes was a reliable indicator of affinity change. Although residues in the C-terminal region play a major role in the stabilization of the hsPLA2GIIA/suramin complex, attractive and repulsive hydrophobic and electrostatic interactions with residues throughout the protein together with the adoption of a bent suramin conformation, all contribute to the stability of the complex. Analysis of the h5PLA2GIIA/suramin interactions allows the prediction of the properties of suramin analogues with improved binding and higher affinities which may be candidates for novel phospholipase A(2) inhibitors. (C) 2012 Elsevier Inc. All rights reserved.

ALDH1A2 (RALDH2) genetic variation in human congenital heart disease

Abstract Background Signaling by the vitamin A-derived morphogen retinoic acid (RA) is required at multiple steps of cardiac development. Since conversion of retinaldehyde to RA by retinaldehyde dehydrogenase type II (ALDH1A2, a.k.a RALDH2) is critical for cardiac development, we screened patients with congenital heart disease (CHDs) for genetic variation at the ALDH1A2 locus. Methods One-hundred and thirty-three CHD patients were screened for genetic variation at the ALDH1A2 locus through bi-directional sequencing. In addition, six SNPs (rs2704188, rs1441815, rs3784259, rs1530293, rs1899430) at the same locus were studied using a TDT-based association approach in 101 CHD trios. Observed mutations were modeled through molecular mechanics (MM) simulations using the AMBER 9 package, Sander and Pmemd programs. Sequence conservation of observed mutations was evaluated through phylogenetic tree construction from ungapped alignments containing ALDH8 s, ALDH1Ls, ALDH1 s and ALDH2 s. Trees were generated by the Neighbor Joining method. Variations potentially affecting splicing mechanisms were cloned and functional assays were designed to test splicing alterations using the pSPL3 splicing assay. Results We describe in Tetralogy of Fallot (TOF) the mutations Ala151Ser and Ile157Thr that change non-polar to polar residues at exon 4. Exon 4 encodes part of the highly-conserved tetramerization domain, a structural motif required for ALDH oligomerization. Molecular mechanics simulation studies of the two mutations indicate that they hinder tetramerization. We determined that the SNP rs16939660, previously associated with spina bifida and observed in patients with TOF, does not affect splicing. Moreover, association studies performed with classical models and with the transmission disequilibrium test (TDT) design using single marker genotype, or haplotype information do not show differences between cases and controls. Conclusion In summary, our screen indicates that ALDH1A2 genetic variation is present in TOF patients, suggesting a possible causal role for this gene in rare cases of human CHD, but does not support the hypothesis that variation at the ALDH1A2 locus is a significant modifier of the risk for CHD in humans.

A novel set of ss-N-biaryl ether sulfonamide hydroxamates as potential MMPs inhibitors: Molecular dynamics simulations and molecular properties evaluation

Matrix metalloproteinases (MMPs) constitute a family of zinc-dependent proteases involved in the extracellular matrix degradation. MMP-2 and MMP9 are overexpressed in several human cancer types, including melanoma, thus the development of new compounds to inhibit MMPs' activity is desirable. Molecular dynamic simulation and molecular properties calculations were performed on a set of novel beta-N-biaryl ether sulfonamide-based hydroxamates, reported as MMP-2 and MMP-9 inhibitors, for providing data to develop an exploratory analysis. Thermodynamic, electronic, and steric descriptors have significantly discriminated highly active from moderately and less active inhibitors of MMP-2 whereas apparent partition coefficient at pH 1.5 was also significant for the MMP-9 data set. Compound 47 was considered an outlier in all analysis, indicating the presence of a bulky substituent group in R3 is crucial to this set of inhibitors for the establishment of molecular interactions with the S1 subsite of both enzymes, but there is a limit. (C) 2012 Wiley Periodicals, Inc.

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.

Computer simulation study of collective dynamics in the glass former Ca(NO3)(2)center dot 4H(2)O

Time correlation functions of current fluctuations were calculated by molecular dynamics (MD) simulations in order to investigate sound waves of high wavevectors in the glass-forming liquid Ca(NO3)(2)center dot 4H(2)O. Dispersion curves, omega(k), were obtained for longitudinal (LA) and transverse acoustic (TA) modes, and also for longitudinal optic (LO) modes. Spectra of LA modes calculated by MD simulations were modeled by a viscoelastic model within the memory function framework. The viscoelastic model is used to rationalize the change of slope taking place at k similar to 0.3 angstrom(-1) in the omega(k) curve of acoustic modes. For still larger wavevectors, mixing of acoustic and optic modes is observed. Partial time correlation functions of longitudinal mass currents were calculated separately for the ions and the water molecules. The wavevector dependence of excitation energies of the corresponding partial LA modes indicates the coexistence of a relatively stiff subsystem made of cations and anions, and a softer subsystem made of water molecules. (C) 2012 American Institute of Physics. [http://dx.doi.org/10.1063/1.4751548]

Distribution and molecular characterization of hepatitis C virus (HCV) genotypes in patients with chronic infection from Pernambuco State, Brazil

Hepatitis C virus (HCV) is a public health problem throughout the world and 3% of the world population is infected with this virus. It is estimated that 3-4 millions individuals are being infected every year. It has been estimated that around 1.5% of Brazilian population is anti-HCV positive and the Northeast region showed the highest prevalence in Brazil. The aim of this study was to characterize HCV genotypes circulating in Pernambuco State (PE), Brazil, located in the Northeast region of the country. This study included 85 anti-HCV positive patients followed up between 2004 and 2011. For genotyping, a 380bp fragment of HCV RNA in the NS5B region was amplified by nested PCR. Phylogenetic analysis was conducted using Bayesian Markov chain Monte Carlo simulation (MCMC) using BEAST v.1.5.3. From 85 samples, 63 (74.1%) positive to NS5B fragment were successfully sequenced. Subtype 1b was the most prevalent in this population (42-66.7%), followed by 3a (16-25.4%), 1a (4-6.3%) and 2b (1-1.6%). Twelve (63.1%) and seven (36.9%) patients with HCV and schistosomiasis were infected with subtypes 1b and 3a, respectively. Brazil is a large country with many different population backgrounds; a large variation in the frequencies of HCV genotypes is predictable throughout its territory. This study reports HCV genotypes from Pernambuco State where subtype 1b was found to be the most prevalent. Phylogenetic analysis suggests the presence of the different HCV strains circulating within this population. (C) 2012 Elsevier B.V. All rights reserved.

Numerical simulation of anisotropic polymeric foams

This paper shows in detail the modelling of anisotropic polymeric foam under compression and tension loadings, including discussions on isotropic material models and the entire procedure to calibrate the parameters involved. First, specimens of poly(vinyl chloride) (PVC) foam were investigated through experimental analyses in order to understand the mechanical behavior of this anisotropic material. Then, isotropic material models available in the commercial software Abaqus (TM) were investigated in order to verify their ability to model anisotropic foams and how the parameters involved can influence the results. Due to anisotropy, it is possible to obtain different values for the same parameter in the calibration process. The obtained set of parameters are used to calibrate the model according to the application of the structure. The models investigated showed minor and major limitations to simulate the mechanical behavior of anisotropic PVC foams under compression, tension and multi-axial loadings. Results show that the calibration process and the choice of the material model applied to the polymeric foam can provide good quantitative results and save project time. Results also indicate what kind and order of error one will get if certain choices are made throughout the modelling process. Finally, even though the developed calibration procedure is applied to specific PVC foam, it still outlines a very broad drill to analyze other anisotropic cellular materials.

Numerical simulation of drop impact and jet buckling problems using the eXtended Pom-Pom model

This work presents numerical simulations of two fluid flow problems involving moving free surfaces: the impacting drop and fluid jet buckling. The viscoelastic model used in these simulations is the eXtended Pom-Pom (XPP) model. To validate the code, numerical predictions of the drop impact problem for Newtonian and Oldroyd-B fluids are presented and compared with other methods. In particular, a benchmark on numerical simulations for a XPP drop impacting on a rigid plate is performed for a wide range of the relevant parameters. Finally, to provide an additional application of free surface flows of XPP fluids, the viscous jet buckling problem is simulated and discussed. (C) 2011 Elsevier B.V. All rights reserved.

Electronic Properties of Water in Liquid Environment. A Sequential QM/MM Study Using the Free Energy Gradient Method

There is a continuous search for theoretical methods that are able to describe the effects of the liquid environment on molecular systems. Different methods emphasize different aspects, and the treatment of both the local and bulk properties is still a great challenge. In this work, the electronic properties of a water molecule in liquid environment is studied by performing a relaxation of the geometry and electronic distribution using the free energy gradient method. This is made using a series of steps in each of which we run a purely molecular mechanical (MM) Monte Carlo Metropolis simulation of liquid water and subsequently perform a quantum mechanical/molecular mechanical (QM/MM) calculation of the ensemble averages of the charge distribution, atomic forces, and second derivatives. The MP2/aug-cc-pV5Z level is used to describe the electronic properties of the QM water. B3LYP with specially designed basis functions are used for the magnetic properties. Very good agreement is found for the local properties of water, such as geometry, vibrational frequencies, dipole moment, dipole polarizability, chemical shift, and spin-spin coupling constants. The very good performance of the free energy method combined with a QM/MM approach along with the possible limitations are briefly discussed.

Modeling and simulation of severe slugging with mass transfer effects

A mathematical model and numerical simulations are presented to investigate the dynamics of gas, oil and water flow in a pipeline-riser system. The pipeline is modeled as a lumped parameter system and considers two switchable states: one in which the gas is able to penetrate into the riser and another in which there is a liquid accumulation front, preventing the gas from penetrating the riser. The riser model considers a distributed parameter system, in which movable nodes are used to evaluate local conditions along the subsystem. Mass transfer effects are modeled by using a black oil approximation. The model predicts the liquid penetration length in the pipeline and the liquid level in the riser, so it is possible to determine which type of severe slugging occurs in the system. The method of characteristics is used to simplify the differentiation of the resulting hyperbolic system of equations. The equations are discretized and integrated using an implicit method with a predictor-corrector scheme for the treatment of the nonlinearities. Simulations corresponding to severe slugging conditions are presented and compared to results obtained with OLGA computer code, showing a very good agreement. A description of the types of severe slugging for the three-phase flow of gas, oil and water in a pipeline-riser system with mass transfer effects are presented, as well as a stability map. (C) 2011 Elsevier Ltd. All rights reserved.

Recoupled separated-local-field experiments and applications to study intermediate-regime molecular motions

A specific separated-local-field NMR experiment, dubbed Dipolar-Chemical-Shift Correlation (DIPSHIFT) is frequently used to study molecular motions by probing reorientations through the changes in XH dipolar coupling and T-2. In systems where the coupling is weak or the reorientation angle is small, a recoupled variant of the DIPSHIFT experiment is applied, where the effective dipolar coupling is amplified by a REDOR-like pi-pulse train. However, a previously described constant-time variant of this experiment is not sensitive to the motion-induced T-2 effect, which precludes the observation of motions over a large range of rates ranging from hundreds of Hz to around a MHz. We present a DIPSHIFT implementation which amplifies the dipolar couplings and is still sensitive to T-2 effects. Spin dynamics simulations, analytical calculations and experiments demonstrate the sensitivity of the technique to molecular motions, and suggest the best experimental conditions to avoid imperfections. Furthermore, an in-depth theoretical analysis of the interplay of REDOR-like recoupling and proton decoupling based on Average-Hamiltonian Theory was performed, which allowed explaining the origin of many artifacts found in literature data. (C) 2012 Elsevier Inc. All rights reserved.