Multi-phase Boltzmann weighting: accounting for local inhomogeneity in molecular simulations of water–octanol partition coefficients in the SAMPL6 challenge

Journal of Computer-Aided Molecular Design - Accurately computing partition coefficients is a pivotal part of drug discovery. Specifically, octanol–water partition coefficients can provide...     

SAMPL7 blind challenge: quantum–mechanical prediction of partition coefficients and acid dissociation constants for small drug-like molecules

The physicochemical properties of a drug molecule determine the therapeutic effectiveness of the drug. Thus, the development of fast and accurate theoretical approaches for the prediction of such properties is inevitable. The participation to the SAMPL7 challenge is based on the estimation of logP coefficients and pK_a values of small drug-like sulfonamide derivatives. Thereby, quantum mechanical calculations were carried out in order to calculate the free energy of solvation and the transfer energy of 22 drug-like compounds in different environments (water and n-octanol) by employing the SMD solvation model. For logP calculations, we studied eleven different methodologies to calculate the transfer free energies, the lowest RMSE value was obtained for the M06L/def2-TZVP//M06L/def2-SVP level of theory. On the other hand, we employed an isodesmic reaction scheme within the macro pK_a framework; this was based on selecting reference molecules similar to the SAMPL7 challenge molecules. Consequently, highly well correlated pK_a values were obtained with the M062X/6–311+G(2df,2p)//M052X/6–31+G(d,p) level of theory.

     

Blind prediction of cyclohexane–water distribution coefficients from the SAMPL5 challenge

In the recent SAMPL5 challenge, participants submitted predictions for cyclohexane/water distribution coefficients for a set of 53 small molecules. Distribution coefficients (log D) replace the hydration free energies that were a central part of the past five SAMPL challenges. A wide variety of computational methods were represented by the 76 submissions from 18 participating groups. Here, we analyze submissions by a variety of error metrics and provide details for a number of reference calculations we performed. As in the SAMPL4 challenge, we assessed the ability of participants to evaluate not just their statistical uncertainty, but their model uncertainty—how well they can predict the magnitude of their model or force field error for specific predictions. Unfortunately, this remains an area where prediction and analysis need improvement. In SAMPL4 the top performing submissions achieved a root-mean-squared error (RMSE) around 1.5 kcal/mol. If we anticipate accuracy in log D predictions to be similar to the hydration free energy predictions in SAMPL4, the expected error here would be around 1.54 log units. Only a few submissions had an RMSE below 2.5 log units in their predicted log D values. However, distribution coefficients introduced complexities not present in past SAMPL challenges, including tautomer enumeration, that are likely to be important in predicting biomolecular properties of interest to drug discovery, therefore some decrease in accuracy would be expected. Overall, the SAMPL5 distribution coefficient challenge provided great insight into the importance of modeling a variety of physical effects. We believe these types of measurements will be a promising source of data for future blind challenges, especially in view of the relatively straightforward nature of the experiments and the level of insight provided.     

Absolute binding free energy calculations of CBClip host–guest systems in the SAMPL5 blind challenge

Herein, we report the absolute binding free energy calculations of CBClip complexes in the SAMPL5 blind challenge. Initial conformations of CBClip complexes were obtained using docking and molecular dynamics simulations. Free energy calculations were performed using thermodynamic integration (TI) with soft-core potentials and Bennett’s acceptance ratio (BAR) method based on a serial insertion scheme. We compared the results obtained with TI simulations with soft-core potentials and Hamiltonian replica exchange simulations with the serial insertion method combined with the BAR method. The results show that the difference between the two methods can be mainly attributed to the van der Waals free energies, suggesting that either the simulations used for TI or the simulations used for BAR, or both are not fully converged and the two sets of simulations may have sampled difference phase space regions. The penalty scores of force field parameters of the 10 guest molecules provided by CHARMM Generalized Force Field can be an indicator of the accuracy of binding free energy calculations. Among our submissions, the combination of docking and TI performed best, which yielded the root mean square deviation of 2.94 kcal/mol and an average unsigned error of 3.41 kcal/mol for the ten guest molecules. These values were best overall among all participants. However, our submissions had little correlation with experiments.     

On the fly estimation of host–guest binding free energies using the movable type method: participation in the SAMPL5 blind challenge

We review our performance in the SAMPL5 challenge for predicting host–guest binding affinities using the movable type (MT) method. The challenge included three hosts, acyclic Cucurbit[2]uril and two octa-acids with and without methylation at the entrance to their binding cavities. Each host was associated with 6–10 guest molecules. The MT method extrapolates local energy landscapes around particular molecular states and estimates the free energy by Monte Carlo integration over these landscapes. Two blind submissions pairing MT with variants of the KECSA potential function yielded mean unsigned errors of 1.26 and 1.53 kcal/mol for the non-methylated octa-acid, 2.83 and 3.06 kcal/mol for the methylated octa-acid, and 2.77 and 3.36 kcal/mol for Cucurbit[2]uril host. While our results are in reasonable agreement with experiment, we focused on particular cases in which our estimates gave incorrect results, particularly with regard to association between the octa-acids and an adamantane derivative. Working on the hypothesis that differential solvation effects play a role in effecting computed binding affinities for the parent octa-acid and the methylated octa-acid and that the ligands bind inside the pockets (rather than on the surface) we devised a new solvent accessible surface area term to better quantify solvation energy contributions in MT based studies. To further explore this issue a, molecular dynamics potential of mean force (PMF) study indicates that, as found by our docking calculations, the stable binding mode for this ligand is inside (rather than surface bound) the octa-acid cavity whether the entrance is methylated or not. The PMF studies also obtained the correct order for the methylation-induced change in binding affinities and associated the difference, to a large extent to differential solvation effects. Overall, the SAMPL5 challenge yielded in improvements our solvation modeling and also demonstrated the need for thorough validation of input data integrity prior to any computational analysis.     

Binding affinities in the SAMPL3 trypsin and host–guest blind tests estimated with the MM/PBSA and LIE methods

We have estimated affinities for the binding of 34 ligands to trypsin and nine guest molecules to three different hosts in the SAMPL3 blind challenge, using the MM/PBSA, MM/GBSA, LIE, continuum LIE, and Glide score methods. For the trypsin challenge, none of the methods were able to accurately predict the experimental results. For the MM/GB(PB)SA and LIE methods, the rankings were essentially random and the mean absolute deviations were much worse than a null hypothesis giving the same affinity to all ligand. Glide scoring gave a Kendall's τ index better than random, but the ranking is still only mediocre, τ = 0.2. However, the range of affinities is small and most of the pairs of ligands have an experimental affinity difference that is not statistically significant. Removing those pairs improves the ranking metric to 0.4-1.0 for all methods except CLIE. Half of the trypsin ligands were non-binders according to the binding assay. The LIE methods could not separate the inactive ligands from the active ones better than a random guess, whereas MM/GBSA and MM/PBSA were slightly better than random (area under the receiver-operating-characteristic curve, AUC = 0.65-0.68), and Glide scoring was even better (AUC = 0.79). For the first host, MM/GBSA and MM/PBSA reproduce the experimental ranking fairly good, with τ = 0.6 and 0.5, respectively, whereas the Glide scoring was considerably worse, with a τ = 0.4, highlighting that the success of the methods is system-dependent.     

Three-dimensional diabatic models for the ππ* → nπ* excited-state decay of uracil derivatives in solution

Uracil and its derivatives strongly absorb UV light but photodamage is hampered through effective non-adiabatic decay channels. As a first step towards a quantum dynamical (QD) study of the decay route of the photoexcited ππ* state to the underlying nπ* state, here we present our procedure to build a reliable reduced-dimensionality model of the decay process, and we discuss its theoretical foundation. We established the three most important nuclear coordinates for the decay process and we computed the S ₁ and S ₂ excited-state potential energy surfaces of Uracil and 5-fluoro-Uracil in acetonitrile and in water at TD-DFT level, describing the solvent in the frame of polarizable continuum model. Through a property-based diabatization we obtained the diabatic ππ* and nπ* states’ energies and coupling and we fitted them to analytical functions of the nuclear coordinates. We show how these diabatic models can be utilized for QD simulations of the ππ* → nπ* decay.     

Use of the three-phase model and headspace analysis for the facile determination of all partition/association constants for highly volatile solute–cyclodextrin–water systems

A versatile method for measuring the partition coefficients of volatile analytes with an aqueous pseudophase using headspace gas chromatography is reported. A “three-phase” model accounts for all equilibria present in the system, including the partitioning of the analyte in the gas and aqueous phases to the pseudophase. This method is applicable to a wide variety of volatile analytes and aqueous pseudophases, providing that sufficient pseudophase may be used to reduce the analyte partial pressure. Generally, the method offers good reproducibility and high sensitivity. The associations of five volatile analytes (hydrogen sulfide, methanethiol, dimethyl sulfide, dichloromethane, and ethyl ether) with various cyclodextrins were examined. All analytes were found to partition preferentially to the cyclodextrin pseudophase compared to the aqueous phase. In addition, several analyte–cyclodextrin combinations formed insoluble complexes in solution that enhanced the extraction of the analyte from the gas and aqueous phases. Derivatization of the cyclodextrins generally decreased the extent of analyte–cyclodextrin interaction.     

Application of the ABEEM/MM model in studying the properties of the water clusters(H_2O)_n(n=7-10)

ABEEM/MM model has been applied to compute the various properties characterizing water clusters(H2O) n(n = 7-10) ,such as optimized geometries,the hydrogen bonds number,cluster interaction en-ergies,stabilities,ABEEM charge distributions,dipole moments,structural parameters,and so on,and to describe the transition reflected by the hexamer region from two-dimensional(from dimer to pen-tamer) to three-dimensional structures(for clusters larger than the hexamer) .     

Study of water clusters in the n = 2–34 size regime, based on the ABEEM/MM model

Various properties of water clusters in the n = 2–34 size regime with the change of cluster size have been systemically explored based on the newly developed flexible-body and charge-fluctuating ABEEM/MM water potential model. The ABEEM/MM water model is to take ABEEM charges of all atoms, bonds, and lone-pairs of water molecules into the intermolecular electrostatic interaction term in molecular mechanics. The computed correlating properties characterizing water clusters (H₂O) _n (n = 2–34) include optimal structures, structural parameters, ABEEM charge distributions, binding energies, hydrogen bonds, dipole moments, and so on. The study of optimal structures shows that the ABEEM/MM model can correctly predict the following important structural features, such as the transition from two-dimensional (from dimer to pentamer) to three-dimensional (for clusters larger than the hexamer) structures at hexamer region, the transition from cubes to cages at dodecamer (H₂O)₁₂, the transition from all-surface (all water molecules on the surface of the cluster) to one water-centered (one water molecule at the center of the cluster, fully solvated) structures at (H₂O)₁₇, the transition from one to two internal molecules in the cage at (H₂O)₃₃, and so on. The first three structural transitions are in good agreement with those obtained from previous work, while the fourth transition is different from that identified by Hartke. Subsequently, a systematic investigation of structural parameters, ABEEM charges, energetic properties, and dipole moments of water clusters with increasing cluster size can provide important reference for describing the objective trait of hydrogen bonds in water cluster system, and also provide a strong impetus toward understanding how the water clusters approach the bulk limit.     

Optimization of the liquid scintillation counting technique for the European interlaboratory comparison on gross α/β activity concentrations in water

A liquid scintillation counting (LSC) measurement method optimization for the gross α/β activity analysis in drinking waters with different chemical and radionuclide composition was performed. The optimized method was suitable to provide gross radioactivity results in drinking waters with the levels of the accuracy and precision similar to those obtained using other radioactivity screening techniques. Robust LSC results contributed to the calculation of gross α/β activity reference values of EC-JRC interlaboratory comparison water samples in 2012. Some of the most common errors in the determination of the gross radioactivity using the LSC are presented.

     

High-resolution gas chromatography retention data as a basis for estimation of the octanol–water distribution coefficients (<Emphasis Type="Italic">K</Emphasis>ow) of PCB: the effect of experimental conditions

The semi-experimental approach to approximating physicochemical data relevant to environmental distribution (vapor pressure and gas–octanol distribution) by correlation with gas chromatography (GC) retention data has been extended to the determination of Kow values. We estimated Kow values >10⁴ for polychlorinated biphenyls (PCB), which are often derived by liquid chromatography, by correlation with gas chromatographic retention data. Selecting a set of reference compounds with known Kow values for relative retention time (RRT) correlation enables easy and accurate semi-empirical calculation of further Kow values for a given group of congeners. The RRT/log Kow correlation is validated in this paper with regard to the following gas chromatographic conditions: (1) isothermal versus temperature-programmed elution, (2) the possible effect of the polarity of the stationary phase, and (3) the effect of the format of the standardized GC retention data. The advantages of our Kow(GC) method can be summarized as follows: complex mixtures can be analyzed, only amounts in the nanogram-range or less are required, Kow values of isomers can be determined and the exact structure of compounds need not be known. Normalized GC retention data of persistent organic pollutants are readily available. The quality of the Kow values obtained by the GC method compares well with that for other Kow estimation methods. It depends mainly on the accuracy of the Kow data of the structurally correlated compounds used as standards for the correlation cohort. The Kow(GC) data for all 209 PCB congeners are given.Dedicated to the memory of Wilhelm Fresenius     

Electrochemical DNA nano-biosensor for the detection of genotoxins in water samples简

In the present study, a disposable electrochemical DNA nano-biosensor is proposed for the rapid detection of genotoxic compounds and bio-analysis of water pollution. The DNA nano-biosensor is prepared by immobilizing DNA on Au nanoparticles and a self-assembled monolayer of cysteamine modified Au electrode. The assembly processes of cysteamine, Au nanoparticles and DNA were characterized by cyclic voltammetry （CV）. The Au nanoparticles enhanced DNA immobilization resulting in an increased guanine signal. The interaction of the analyte with the immobilized DNA was measured through the variation of the electrochemical signal of guanine by square wave voltammetry （SWV）. The biosensor was able to detect the known genotoxic compounds： 2-anthramine, acridine orange and 2- naphthylamine with detection limits of 2, 3 and 50 nmol/L, respectively. The biosensor was also used to test actual water samples to evaluate the contamination level. Additionally, the comparison of results from the classical genotoxiciw bioassay has confirmed the applicability of the method for real samoles.     

Predictive/fitting capabilities of differential constitutive models for polymer melts—reduction of nonlinear parameters in the eXtended Pom-Pom model

A phenomenological modification of the eXtended Pom-Pom (XPP) model is proposed with the aim to reduce the number of free nonlinear parameters. The modified XPP model includes three parameters per mode in total (two linear viscoelastic parameters—linear relaxation time λ and shear modulus G, and one nonlinear parameter). The original XPP model contains five parameters (two linear viscoelastic parameters and three nonlinear ones, one nonlinear parameter participates in the second normal stress difference prediction). The predictive/fitting capabilities of the modified model are compared with the Giesekus, eXtended Pom-Pom, and modified Leonov models using various low-density PE materials in steady and transient shear and uniaxial elongational flows. It has been found that the modified model is capable of predicting/fitting the rheological properties, with the exception of the second normal stress difference, for studied LDPE materials with sufficient accuracy, including strain hardening in uniaxial elongational flow.     

o-Iodoxybenzoic acid (IBX): a versatile reagent for the synthesis of N-substituted pyrroles mediated by β-cyclodextrin in water

o-Iodoxybenzoic acid (IBX), a very mild and efficient hypervalent iodine(V) reagent, aromatizes diversely substituted 1-benzylpyrrolidines and N-substituted l-proline analogues to the corresponding substituted pyrroles in good to excellent yields under mild conditions mediated by β-cyclodextrin in water at room temperature. To the best of our knowledge, this is the first report on IBX, promoting complete aromatization leading to N-benzylpyrroles from the corresponding saturated five membered heterocyclic derivatives in water medium.     

Application of Nylon6/Polypyrrole core–shell nanofibres mat as solid-phase extraction adsorbent for the determination of atrazine in environmental water samples

A novel solid-phase extraction (SPE) system, based on a new sorbent of Nylon6/Polypyrrole (PA6/PPy) core–shell nanofibres mat and a new packing format of SPE disks, is presented in this paper. A series of related parameters that may affect the efficiency, such as the kind of eluent and its volume, the amount of nanofibres mat, ionic strength, pH of the sample, flow rate of the sample and volume of the sample, have been investigated systematically. Under the optimised conditions, the target analyte in 10 mL water samples can be completely extracted by a 3.0 mg PA6/PPy nanofibres mat and easily eluted by 400 µL acetonitrile. Around 20 µL elution was injected directly to HPLC-UV for determination, without further concentration. Besides, the nanofibres mat could be repeatedly used up to six cycles. Satisfactory linearity was achieved in the range of 0.1–40.0 ng/mL with a correlation coefficient of 0.9999. The limit of detection (LOD) (3 S/N) was 0.03 ng/mL, which could meet the determination requirements of atrazine as per the European Union legislation, US. Safe Drinking Water Act and the State Environmental Protection Administration of China. The simple, effective and economic method was proposed for the determination of atrazine in environmental water at trace level. The recoveries ranged from 94.73 to 114.92%, with relative standard deviations (RSDs) of 2.5–4.2%, and were obtained from tap water and lake water samples with atrazine at 2.0 ng/mL, suggesting the actual feasibility of the proposed method in environmental water samples.     

Application of high-performance liquid chromatography–tandem mass spectrometry with a quadrupole/linear ion trap instrument for the analysis of pesticide residues in olive oil

This article describes the development of an enhanced liquid chromatography-mass spectrometry (LC-MS) method for the analysis of pesticides in olive oil. One hundred pesticides belonging to different classes and that are currently used in agriculture have been included in this method. The LC-MS method was developed using a hybrid quadrupole/linear ion trap (QqQ(LIT)) analyzer. Key features of this technique are the rapid scan acquisition times, high specificity and high sensitivity it enables when the multiple reaction monitoring (MRM) mode or the linear ion-trap operational mode is employed. The application of 5 ms dwell times using a linearly accelerating (LINAC) high-pressure collision cell enabled the analysis of a high number of pesticides, with enough data points acquired for optimal peak definition in MRM operation mode and for satisfactory quantitative determinations to be made. The method quantifies over a linear dynamic range of LOQs (0.03-10 microg kg(-1)) up to 500 microg kg(-1). Matrix effects were evaluated by comparing the slopes of matrix-matched and solvent-based calibration curves. Weak suppression or enhancement of signals was observed (<15% for most-80-of the pesticides). A study to assess the identification criteria based on the MRM ratio was carried out by comparing the variations observed in standard vs matrix (in terms of coefficient of variation, CV%) and within the linear range of concentrations studied. The CV was lower than 15% when the response observed in solvent was compared to that in olive oil. The limit of detection was < or =10 microg kg(-1) for five of the selected pesticides, < or =5 microg kg(-1) for 14, and < or =1 microg kg(-1) for 81 pesticides. For pesticides where additional structural information was necessary for confirmatory purposes-in particular at low concentrations, since the second transition could not be detected-survey scans for enhanced product ion (EPI) and MS3 were developed.     

Tetrahydrofuran–water extraction,in-line clean-up and selective liquid chromatography/tandem mass spectrometry for the quantitation of perfluorinated compounds in food at the low picogram per gram level

A new solvent extraction system was developed for extraction of PFCs from food. The extraction is carried out with 75:25 (v/v) tetrahydrofuran:water, a solvent mixture that provides an appropriate balance of hydrogen bonding, dispersion and dipole–dipole interactions to efficiently extract PFCs with chains containing 4–14 carbon atoms from foods. This mixture provided recoveries above 85% from foods including vegetables, fruits, fish, meat and bread; and above 75% from cheese. Clean-up with a weak anion exchange resin and Envi-carb SPE, which were coupled in line for simplicity, was found to minimize matrix effects (viz. enhancement or suppression of electrospray ionization). The target analytes (PFCs) were resolved on a perfluorooctyl phase column that proved effective in separating mass interferences for perfluorooctane sulfonate (PFOS) in fish and meat samples. The mass spectrometer was operated in the negative electrospray ionization mode and used to record two transitions per analyte and one per mass-labeled method internal standard. The target PFCs were quantified from solvent based calibration curves. The limits of detection (LODs) were as low as 1–5 pg analyte g⁻¹ food; by exception, those for C₄ and C₅ PFCs were somewhat higher (25–30 pg g⁻¹) owing to their less favourable mass response. To the best of our knowledge these are among the best LODs for PFCs in foods reported to date. The analysis of a variety of foods revealed contamination with PFCs at levels from 4.5 to 75 pg g⁻¹ in 25% of samples (fish and packaged spinach). C₁₀–C₁₄ PFCs were found in fish, which testifies to the need to control long-chain PFCs in this type of food. The proposed method is a useful tool for the development of a large-scale database for the presence of PFCs in foods.     

Hollow nanoshell-sphere Fe@Fe/Pd reactors: a magnetically recoverable catalyst for the C<Subscript>sp</Subscript>–S cross-coupling reactions in water

The hollow Pd–PVP–Fe nanosphere and Fe–PVP nanoparticle catalysts were synthesized by thermal method. Mixing of two metallic nanocatalysts was applied in the C_sp–S cross-coupling reactions between diphenyl disulfide and phenylacetylene under mild conditions in water. Results show that bi-catalytic system has higher catalytic efficiencies than their monocatalytic systems due to synergy between two catalysts. Order of adding two metallic catalysts were adjusted into the coupling reaction medium. Therefore, various bi-catalytic systems were obtained and characterized by XRD, SEM, EBSD, EDX, UV–Vis spectra, and particle size analyzer. Under special order of adding, the obtained hollow nanoshell-sphere Fe@Fe/Pd reactor showed higher catalytic activity in the coupling reaction compared to other bi-catalytic systems. The C_sp–S coupling products obtained of various diaryl disulfides and phenylacetylene at presence Fe@Fe/Pd (only 7.3?×?10^?5 mmol Pd) catalyst with moderate to high yields in water solvent and mild reaction conditions. After the reaction, the catalyst/product(s) separation could be easily achieved with an external magnet and more than 95% of catalyst could be recovered. The recovered catalyst was characterized by XRD, SEM, EBSD, EDX, and UV–Vis spectra. The Fe@Fe/Pd was reused at least six repeating cycles without any loss of its high catalytic activity. Tuning morphology and chemical composition of bi-catalytic system are key mainstays of high activity of Fe@Fe/Pd in repeating cycles of cross-coupling reactions.