Molecular recognition probes of solvation thermodynamics in solvent mixtures

High-throughput UV-Vis experiments using four molecular recognition-based probes, made by the combination of two hydrogen bond acceptors, tri-n-butylphosphine oxide and N,N'-bis(2-ethylhexyl)acetamide, and two hydrogen bond donors, 4-phenylazophenol and 4-nitrophenol, were performed. The association constants for the 1 : 1 H-bond interaction involved in each probe system were measured in mixtures of a polar and non-polar solvent, di-n-hexyl ether and n-octane, respectively. Similar behaviour was observed for all four systems. When the concentration of the polar solvent was low, the association constant was identical to that observed in pure n-octane. However, once the concentration of the polar solvent exceeded a threshold, the association constant decreased linearly with the concentration of di-n-hexyl ether. Selective solvation in mixtures can be understood based on the competition between the multiple competing equilibria in the system. In this case, solvation thermodynamics are dominated by competition of the ether for solvation of H-bond donors. For the more polar solute, 4-nitrophenol, the selective solvation starts at lower concentrations of the polar solvent compared with the less polar solute, 4-phenylazophenol. Thus the speciation and hence the properties of systems containing multiple solutes and multiple solvents can be estimated from the H-bond properties and the concentrations of the individual functional groups.     

Fluorinated nitroxides as ESR probes of solvation

Some newly synthesized fluorinated nitroxides, such as t-butyl perfluoroalkyl nitroxides Bu^tN(O) R_f (R_f=CF₃, 5; C₂F₅, 6; n-C₃F₇, 7) and s-butyl perfluoroacyl nitroxides Bu^sN(O) COR_f (R_f=CF₃, 9; n-C₃F₇, 10) have been employed as ESR probes of solvation in different common organic solvents. In aprotic solvents, the measured a_N values for each of the nitroxyl probes show a linear correlation with the cybotactic polar solvent parameters E_T (Dimroth) and Z (Kosowar), i.e. a_N=bE_T+c, and a_N=b′Z+c′. The physical significance for the slope (b or b′), the slope×E_T or slope×Z, the extrapolated intercept on a_N axis, c or c′, are linked, respectively, to the sensitivity of a specific nitroxide toward solvation, the magnitude of the overall solvation effect on the a_N value, and the intrinsic a_N value of each nitroxide in the ideal gaseous state. The intercept on the a_N axis may also serve as a new measure of electronegativity for perfluoroalkyl groups, CF₃, C₂F₅, n-C₃F₇, and perfluoroacyl groups, CF₃CO, n-C₃F₇CO. In protic solvents, i.e. alcohols and carboxylic acids, however, a_N values of all the probes, kept almost no change with the increase in E_T and Z. Furthermore, the plots of a_N versus non-cybotactic solvent constants, such as dipolar moment (μ) and dielectric constant (ε), all show random variations.     

Structure and solvation properties of aqueous sulfobetaine micelles in the presence of organic spin probes: a Molecular Dynamics simulation study

Structural and mechanical-dynamical information on a micelle formed by 72 monomers of N-dodecyl-N,N-dimethyl-3-ammonio-1-propanesulfonate (SB 3–12) in water solution have been obtained through Molecular Dynamics simulations. Additional simulations have been carried out to evaluate whether and to what extent the structural features of the micelle are affected by the presence of a spin probe, typically utilized for the experimental characterization of these, rather complex, systems. Results indicate that the micelle shows a spherical shape not heavily influenced by the presence of the probe which only produces a slight volume increase. Further analysis also indicates that the probe, although inducing scarce alterations at the micelle-solvent interface, heavily influences the micelle core which appears less stable (more fluctuating) and less hydrated. Finally, analysis of residence times of water indicate—in line with many previous studies—the presence of a dual population characterized by different interactions with micelle interior.     

The use of infrared probes in solvation studies: Acetone in mixed protic-aprotic solvents

Infrared spectra ot acetone in the CO stretching region have been studied as a function of the composition of a range of mixed protic-aprotic solvents. For methanolic systems, equilibria between hydrogen-bonded and non hydrogen-bonded acetone dominate the spectral changes, but for aqueous systems at least four distinct components need to be considered.     

Molecular recognition phenomena in polyelectrolyte systems

The term “molecular recognition” is commonly used to describe various specific interactions, sometimes being not well defined. Let's assume that some species A can separately interact with either species B₁, or B₂, (or B₃, B₄ etc.) forming A·B₁, or A·B₂, (or A·B₃, or A·B₄ etc.) complexes. Here we say “recognition” assuming selective complexation of A with B₁ in the mixture containing also B₂ (B₃, B₄… etc.). At the same time it means discrimination of all other B species except B₁.     

Hydrogen-bonding molecular ruler surfactants as probes of specific solvation at liquid/liquid interfaces

Resonance-enhanced, second harmonic generation (SHG) is used to measure the electronic structure of solutes sensitive to specific solvation adsorbed to liquid/liquid and liquid/solid interfaces. Here, specific solvation refers to solvent–solute interactions that are directional and localized. N-methyl-p-methoxyaniline (NMMA) is a solute whose first allowed electronic transition wavelength remains almost constant (∼315 nm) in non-hydrogen-bonding solvents regardless of solvent polarity. However, in hydrogen-bond-accepting solvents such as dimethylsulfoxide, NMMA’s absorbance shifts to longer wavelengths (320 nm), whereas in hydrogen-bond-donating solvents (e.g., water), the absorbance shifts to shorter wavelengths (∼300 nm). SHG experiments show that at alkane/silica interfaces, surface silanol groups serve as moderately strong hydrogen-bond donors as evidenced by NMMA’s absorbance of 307 nm. At the carbon tetrachloride/water interface, NMMA absorbance also shifts to slightly shorter wavelengths (298 nm) implying that water molecules at this liquid/liquid interface are donating strong hydrogen bonds to the adsorbed NMMA solutes. In contrast, experiments using newly developed molecular ruler surfactants with NMMA as a model hydrophobic solute and a hydrophilic, cationic headgroup imply that, as NMMA migrates across an aqueous/alkane interface, it carries with it water that functions as a hydrogen-bond-accepting partner.     

Capillary electrophoresis of inorganic anions in hydro-organic media. Influence of ion-pairing and solvation phenomena

The capillary electrophoresis separation of four inorganic anions (NO3-, I-, Br- and SCN-) was investigated over the whole range of methanol-water mixture composition. As the separation selectivity was strongly dependent on the solvent composition, the influence of ion-pairing and solvation phenomena was examined in depth in an attempt to explain this modification. First, a series of experiments was performed in methanolic background electrolytes, with counter-ions of different size. Ion-pair formation involving electrolyte ions was assessed to allow for a correction for free electrolyte ion concentration. Ion-pair formation constants between each inorganic anion and electrolyte counter-ion were next determined from the variations of the anion mobility as a function of the free counter-ion concentration. In view of the low values obtained, ion-pair formation alone failed to explain the selectivity variations. Solvation phenomena were then investigated with the help of a theoretical quantum model, the density functional theory (DFT), coupled with a polarizable continuum model to mime non-specific solvent effects. Whereas this model proved successful at predicting the mobility order at infinite dilution in water, it failed to predict the correct order in methanol.     

Molecular beacon probes of oligonucleotides photodamaged by psoralen

Ultraviolet A (UVA)-irradiated 4'-hydroxymethyl-4,5',8-trimethyl psoralen (HMT) in the presence of a poly-dT(17) and dA(7) TTA(8) oligonucleotides produces HMT-dT(17) and HMT-dA(7) TTA(8) adducts in aqueous solution. In this article, we determine whether these HMT-dT(17) and HMT-dA(7) TTA(8) adducts can be detected with a molecular beacon (MB) probe. We measure the degree of damage in dT(17) and dA(7) TTA(8) solutions containing UVA-activated HMT via monitoring the decrease in MB fluorescence. Photoproduct formation is confirmed by MALDI-TOF MS (matrix-assisted laser desorption/ionization time-of-fight mass spectrometry measurements) and absorption spectroscopy. The MB fluorescence decreases upon UVA irradiation in the presence of HMT with a single-exponential time constants of 114.2 ± 6.5 min for HMT-dT(17) adducts and 677.8 ± 181.8 min for HMT-dA(7) TTA(8) adducts. Our results show that fluorescent MB probes are a selective, robust and accurate tool for detecting UVA-activated HMT-induced DNA damage.     

Molecular dynamics study of the solvation of calcium carbonate in water

We performed molecular dynamics simulations of diluted solutions of calcium carbonate in water. To this end, we combined and tested previous polarizable models. The carbonate anion forms long-living hydrogen bonds with water and shows an amphiphilic character, in which the water molecules are expelled in a region close to its C(3) symmetry axis. The calcium cation forms a strongly bound ion pair with the carbonate. The first hydration shell around the CaCO(3) pair is found to be very similar to the location of the water molecules surrounding CaCO(3) in ikaite, the hydrated mineral.     

Molecular density functional theory of solvation: from polar solvents to water

A classical density functional theory approach to solvation in molecular solvent is presented. The solvation properties of an arbitrary solute in a given solvent, both described by a molecular force field, can be obtained by minimization of a position and orientation-dependent free-energy density functional. In the homogeneous reference fluid approximation, limited to two-body correlations, the unknown excess term of the functional approximated by the angular-dependent direct correlation function of the pure solvent. We show that this function can be extracted from a preliminary MD simulation of the pure solvent by computing the angular-dependent pair distribution function and solving subsequently the molecular Ornstein-Zernike equation using a discrete angular representation. The corresponding functional can then be minimized in the presence of an arbitrary solute on a three-dimensional cubic grid for positions and Gauss-Legendre angular grid for orientations to provide the solvation structure and free-energy. This two-step procedure is proved to be much more efficient than direct molecular dynamics simulations combined to thermodynamic integration schemes. The approach is shown to be relevant and accurate for prototype polar solvents such as the Stockmayer solvent or acetonitrile. For water, although correct for neutral or moderately charged solute, it tends to underestimate the tetrahedral solvation structure around H-bonded solutes, such as spherical ions. This can be corrected by introducing suitable three-body correlation terms that restore both an accurate hydration structure and a satisfactory energetics.     

Molecular dynamics study of the solvation of an alpha-helical transmembrane peptide by DMSO

A 10-ns molecular dynamics study of the solvation of a hydrophobic transmembrane helical peptide in dimethyl sulfoxide (DMSO) is presented. The objective is to analyze how this aprotic polar solvent is able to solvate three groups of amino acid residues (i.e., polar, apolar, and charged) that are located in a stable helical region of a transmembrane peptide. The 25-residue peptide (sMTM7) used mimics the cytoplasmic proton hemichannel domain of the seventh transmembrane segment (TM7) from subunit a of H(+)-V-ATPase from Saccharomyces cerevisiae. The three-dimensional structure of peptide sMTM7 in DMSO has been previously solved by NMR spectroscopy. The radial and spatial distributions of the DMSO molecules surrounding the peptide as well as the number of hydrogen bonds between DMSO and the side chains of the amino acid residues involved are extracted from the molecular dynamics simulations. Analysis of the molecular dynamics trajectories shows that the amino acid side chains are fully embedded in DMSO. Polar and positively charged amino acid side chains have dipole-dipole interactions with the oxygen atom of DMSO and form hydrogen bonds. Apolar residues become solvated by DMSO through the formation of a hydrophobic pocket in which the methyl groups of DMSO are pointing toward the hydrophobic side chains of the residues involved. The dual solvation properties of DMSO cause it to be a good membrane-mimicking solvent for transmembrane peptides that do not unfold due to the presence of DMSO.     

Molecular complexes and solvation interactions in the reaction of quinone imines with thiols

This study aims to investigate the role of complexation between reagents and the role of solvation of reagents by solvents in the kinetics of chain reactions of quinone imines with thiols. The thermodynamic characteristics of the complexation of quinone imines with thiophenol in CCl₄, chlorobenzene, and ethanol, as well as of the complexation of quinone imines and thiophenol with these solvents were calculated by quantum chemical methods (DFT calculations at the PBE/cc-pVDZ level of theory) and in terms of the additive-multiplicative model. Both approaches give consistent results. The formation of molecular complexes in quinone imine–thiphenol systems is accompanied by a 10–30 kJ mol^–1 decrease in enthalpy and has only a slight effect on the reaction mechanism.     

Molecular theory of critical phenomena in aliphatic carboxylic acid monolayers

A statistical mechanical theory is presented for the behavior of monolayers of aliphatic carboxylic acids at the air/water interface. A lattice fluid model is introduced with monomer states to represent molecules in the all-trans conformation directed perpendicular to the interface, dimer states to represent rotational isomers, and vacant sites or “holes.” Using a Flory–Huggins-type approximation, the temperature and chain length dependences of the monolayer behavior are satisfactorily reproduced for a certain range of parameters. These parameters are compared with those intermolecular energies calculated using the methods of computational quantum chemistry. The agreement thus obtained is fairly satisfactory indicating that the higher-order nature of fatty acid monolayer transitions is due to the onset of the rotational ordering of pairs of chains about their longitudinal axes, while the sensitive temperature dependence is attributed to the flexible nature of fatty acid molecules. Some possible effects due to the presence of the substrate are discussed.     

Molecular beacon probes for the detection of cisplatin-induced DNA damage

Cisplatin (cis-diamminedichloroplatinum(II)) causes crosslinking of DNA at AG and GG sites in cellular DNA, inhibiting replication, and making it a useful anti-cancer drug. Several techniques have been used previously to detect nucleic acid damage but most of these tools are labour-intensive, time-consuming, and/or expensive. Here, we describe a sensitive, robust, and quantitative tool for detecting cisplatin-induced DNA damage by using fluorescent molecular beacon probes (MB). Our results show a decrease of fluorescence in the presence of cisplatin-induced DNA damage, confirmed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). The decrease in fluorescence upon damage scales with the number of AG and GG sites, indicating the ability of MB to quantitatively detect DNA damage by cisplatin.     

Molecular beacon probes of photodamage in thymine and uracil oligonucleotides

Molecular beacons (MB) are becoming more common as sequence-selective detectors of nucleic acids. Although they can easily detect single-base mismatches, they have never been used to directly detect DNA or RNA damage. To measure the degree of ultraviolet (UV) light damage in oligonucleotides, we report a novel MB approach for general detection of photoproducts in UV-irradiated rU17 and dT17 oligonucleotides. With monochromatic UV light irradiation at ca 280 nm under anoxic conditions, the oligonucleotide absorption decays with a single-exponential time constant of 123+/-1 min for rU17 and with double-exponential time constants of 78+/-0.5 min (99%) and 180+/-5 min (0.05%) for dT17 oligonucleotides. Under the same conditions, the MB fluorescence decays more quickly, with single-exponential time constants of 19+/-2 and 26+/-3 min for rU17 and dT17, respectively. Similar kinetics were observed with broadband UV light irradiation of oligonucleotides. The differences in the UV damage kinetics of dT17 and rU17 and their detection by absorption and fluorescence techniques will be discussed in the context of differential instabilities introduced in the nucleic acid-MB duplex by the different photoproducts formed.     

Molecular dynamics study of 2rotaxanes: influence of solvation and cation on co-conformation

The conformational preference of a [2]rotaxane system has been examined by molecular dynamics simulations. The rotaxane wheel consists of two bridged binding components: a cis-dibenzo-18-crown-6 ether and a 1,3-phenyldicarboxamide, and the penetrating axle consists of a central isophthaloyl unit with phenyltrityl capping groups. The influence of solvation on the co-conformation of the [2]rotaxane was evaluated by comparing the conformational flexibility in two solvents: chloroform and dimethyl sulfoxide. Attention was also paid to the effect of cation binding on the dynamical properties of the [2]rotaxane. The conformational stability of the [2]rotaxane was calculated using a MM/PB-SA strategy, and the occurrence of specific motions was examined by essential dynamics analysis. The changes in the co-conformational properties in the two solvents and upon cation binding are discussed in light of the available NMR data. The results indicate that in chloroform solution the [2]rotaxane system exists as a mixture of co-conformational states including some that have hydrogen bonds between axle C=O and wheel NH groups. Analysis of the simulations allow us to hypothesize that the [2]rotaxane's circumrotation motion can occur as the result of a dynamic process that combines a preliminary axle sliding step that breaks these hydrogen bonds and a conformational change in the ester group more distant from the wheel. In contrast, no hydrogen-bonded co-conformation was found in dimethyl sulfoxide, which appears to be due to the preferential formation of hydrogen bonds between the wheel NH groups with solvent molecules. Moreover, the axle experiences notable changes in anisotropic shielding, which would explain why the NMR signals are broadened in this solvent. Insertion of a sodium cation into the crown ether reduces co-conformational flexibility due to an interaction of the axle with the cation. Overall, the results reveal how both solvent and ionic atmosphere can influence the co-conformational preferences of rotaxanes.     

Fragment Molecular Orbital method-based Molecular Dynamics (FMO-MD) as a simulator for chemical reactions in explicit solvation

Fragment Molecular Orbital based-Molecular Dynamics (FMO-MD, Komeiji et al., Chem Phys Lett 2003, 372, 342) is an ab initio MD method suitable for large molecular systems. Here, FMO-MD was implemented to conduct full quantum simulations of chemical reactions in explicit solvation. Several FMO-MD simulations were performed for a sphere of water to find a suitable simulation protocol. It was found that annealing of the initial configuration by a classical MD brought the subsequent FMO-MD trajectory to faster stabilization, and also that use of bond constraint in the FMO-MD heating stage effectively reduced the computation time. Then, the blue moon ensemble method (Sprik and Ciccotti, J Chem Phys 1998, 109, 7737) was implemented and was tested by calculating free energy profiles of the Menschutkin reaction (H3N + CH3Cl --> +H3NCH3 + Cl-) in the presence and absence of the solvent water via FMO-MD. The obtained free energy profiles were consistent with the Hammond postulate in that stabilization of the product by the solvent, namely hydration of Cl-, shifted the transition state to the reactant-side. Based on these FMO-MD results, plans for further improvement of the method are discussed.     

Molecular simulation of binary colloidal mixtures: Gelation and aging phenomena

We investigate the aging dynamics of colloidal depletion gel by computer simulation. In this study, we employ an alternative approach using the effective pair potential to avoid the slow convergence in binary mixtures due to cage effect, and the structural formation of colloidal depletion gels is then clarified. We study the mean square displacement (MSD) of each segment in depletion gels by stochastic molecular dynamic simulations. It is shown that the MSD obeys a power-law, indicating sub-diffusive behavior of depletion gels. We also observe aging phenomena of the colloidal depletion gels from intermediate scattering functions. Power-law behavior of a characteristic time in this system, as a function of a waiting time, is also clarified.