Site-specific solvation determined by intermolecular nuclear Overhauser effect--measurements and molecular dynamics

Site-specific solvation has been determined by intermolecular NOE measurements between solvent and solute. The experimental effect is shown on the four compounds 2-butanol, L-alanyl-L-tryptophan (Ala-Trp), adenosine and the disodium salt of adenosine 5'-monophosphate (5'-AMP) in the two solvents water and dimethyl sulfoxide (DMSO). The strength of NOE transfer correlates with the average distribution of solvent molecules around the corresponding solvation sites represented by the number of solvent molecules in a first solvation sphere, which can be obtained from molecular dynamics simulations in water. Saturation transfer between exchanging protons explains some deviations from this correlation. The NOE transfer measurements provide information on specific solute-solvent interactions and contribute to a better understanding of solvation phenomena. On the basis of a distinct relationship between steric solvation hindrance and the strength of NOE transfer, the application of such measurements for conformational analysis has been demonstrated for the first time.     

Nuclear spin relaxation driven by intermolecular dipolar interactions: the role of solute-solvent pair correlations in the modeling of spectral density functions

Nuclear spin relaxation provides useful information related to the dynamics of molecular systems. When relaxation is driven by intermolecular dipolar interactions, the relevant spectral density functions (SDFs) also have significant contributions, in principle, from distant spins all over the dynamic range typically probed by NMR experiments such as NOESY. In this work, we investigate the intermolecular dipolar spin relaxation as driven by the relative diffusion of solvent and solute molecules taking place under a central force field, and we examine the relevant implications for (preferential) solvation studies. For this purpose, we evaluate the SDFs by employing a numerical approach based on spatial discretization of the time-propagation equation, and we supply an analytical solution for the simplest case of a steplike mean-field potential. Several situations related to different solute-solvent pair correlation functions are examined in terms of static/dynamic effects and relaxation modes, and some conclusions are drawn about the interpretation of NOE measurements. While we confirm previous results concerning the spoiling effect of long-range spins (Halle, B. J. Chem. Phys. 2003, 119, 12372), we also show that SDFs are sufficiently sensitive to pair correlation functions that useful, yet rather complicated, inferences can be made on the nature of the solvation shell.     

Investigation of dipolar-mediated water-protein interactions in microcrystalline Crh by solid-state NMR spectroscopy

Water-protein interactions play a major role in protein folding, structure, and function, and solid-state NMR has recently been shown to be a powerful tool for the site-resolved observation of these interactions in solid proteins. In this article we report investigations on possible water-protein dipolar transfer mechanisms in the microcrystalline deuterated protein Crh by a set of solid-state NMR techniques. Double-quantum (DQ) filtered and edited heteronuclear correlation experiments are used to follow direct dipolar water-protein magnetization transfers. Experimental data reveal no evidence for "solid-like" water molecules, indicating that residence times of solvent molecules are shorter than required for DQ creation, typically a few hundred microseconds. An alternative magnetization pathway, intermolecular cross-relaxation via heteronuclear nuclear Overhauser effects (NOEs), is probed by saturation transfer experiments. The significant additional enhancements observed when irradiating at the water frequency can possibly be attributed to direct heteronuclear water-protein NOEs; however, a contribution from relayed magnetization transfer via chemical exchange or proton-proton dipolar mechanisms cannot be excluded.     

Interactions of trimethylamine N-oxide and water with cyclo-alanylglycine

The osmolyte trimethylamine N-oxide (TMAO) is one of a family of compounds found in living systems that can stabilize biomolecular tertiary structures. As a step in exploring the interactions between this material and polyamino acids, we have determined intermolecular 1H{1H} nuclear Overhauser effects (NOEs) between the protons of cyclo-alanylglycine and protons of solvent components in TMAO-water solutions. Comparison of the results to effects predicted on the basis of the molecular shape of the dipeptide and experimental translational diffusion coefficients suggests that both water and TMAO molecules have properties in the vicinity of the dipeptide that are different from those in the bulk solution. Changes of local concentrations of water and TMAO and changes in the diffusive behavior of these components near the dipeptide are rejected as possible explanations of the discrepancies between observed and calculated Overhauser effects. Rather, it is concluded that TMAO molecules, and the water molecules associated with them, participate to some extent in the formation of long-lived solute-solvent complexes. The aliphatic alcohol tert-butyl alcohol is structurally similar to TMAO. Overhauser effect studies of its interaction with cyclo-alanylglycine in tert-butyl alcohol-water suggest similar kinds of interactions are present in this system but that they are significantly weaker, presumably because of the lower polarity of this alcohol compared to TMAO.     

The pH-dependence of preferential solvation as studied by intermolecular homo- and heteronuclear NOE measurements of adenosine in water–trifluoroethanol mixtures

A study of the state of solvation of the adenine ring in adenosine and adenosine 5-monophosphate disodium salt in water and in a (7.5:2.5) water–TFE mixture has been carried out by measurement of homo- and heteronuclear intermolecular NOE enhancements between water or TFE and the aromatic protons of these compounds. The results give evidence of site specificity in solute–solvent interaction for both solvent systems and preferential solvation of the solute by TFE in the water–TFE mixture. Significant pH dependence of these interactions has been discovered.     

醇类溶剂溶剂化显色极性的理论分析

对一系列醇类溶剂分子进行了理论计算,运用多元线性回归分析方法从分子间相互作用的角度对四种溶剂化显色极性参数(E~T^N,π^*,Py和SPP)进行了理论分析。结果表明,对醇类溶剂而言,参数E~T^N和SPP实质上主要反映的是溶剂的氢键酸性性质;参数π^*中虽然包含了溶剂的极性因素,但同时与溶质-溶剂分子间的电荷转移相互作用有着密切的关系;而参数Py则较好地反映了溶剂的极性性质。     

Structures of protein-protein complexes are docked using only NMR restraints from residual dipolar coupling and chemical shift perturbations

NMR structures of protein-protein and protein-ligand complexes rely heavily on intermolecular NOEs. Recent work has shown that if no significant conformational changes occur upon complex formation residual dipolar coupling can replace most of the NOE restraints in protein-protein complexes, while restraints derived from chemical shift perturbations can largely replace intermolecular NOEs in protein-ligand structures. By combining restraints from chemical shift perturbations with orientation restraints derived from measurements of residual dipolar couplings, we show that the structure of the EIN-HPr complex can be calculated without NOE restraints. The final structure, built from the crystal structures of EIN and HPr in their uncomplexed form and docked only with NMR restraints, places HPr within 2.5 A of the position determined from the mean NMR structure of the complex.     

Association and dissociation of an aqueous amphiphile at elevated temperatures

The hydrophobic interaction is often thought to increase with increasing temperature. Although there is good experimental evidence for decreased aqueous solubility and increased clustering of both nonpolar and amphiphilic molecules as temperature is increased, the detailed nature of the changes in intermolecular interactions with temperature remain unknown. By use of isotope substitution neutron scattering difference measurements on a 0.04 mole fraction solution of tert-butanol in water as the solute clustering passes through a temperature maximum, the changes in local intermolecular structures are examined. Although, as expected, the solute molecules cluster through increased contact between their nonpolar head groups with the exclusion of water, the detailed geometry of the mutual interactions changes as temperature increases. As the clustering breaks up with further temperature increase, the local structures formed do not mirror those that were found in the low-temperature dispersed system: the disassembly process is not the reverse of assembly. The clusters formed by the solute head groups are reminiscent of structures that are found in systems of spherical molecules, modulated by the additional constraint of near-maximal hydrogen bonding between the polar tails of the alcohol and the solvent water. Although the overall temperature behavior is qualitatively what would be expected of a hydrophobically driven system, the way the system resolves the competing interactions and their different temperature dependencies is complex, suggesting it could be misleading to think of the aggregation of aqueous amphiphiles solely in terms of a hydrophobic driving force.     

Molecular probes of solvation phenomena

The properties of the molecules present in any chemical or biological system are dependent on interactions with the environment, and a quantitative understanding of solvation phenomena remains a major challenge. Molecular recognition probes provide a new approach to quantitatively measure the properties of solvents. Traditionally, solvent polarity scales have been based on spectroscopic probes that provide insight into the nature of solvent-solute interactions. This review compares the solvent polarity parameters obtained from the wavelengths of UV/Visible absorption maxima with solute H-bond parameters obtained from the free energies of solution equilibria. The similarity of the solvent and solute H-bond scales leads to a general H-bond scale that uses the same parameters to describe both solvent and solute. The general H-bond scale provides a framework for understanding the relationship between local intermolecular interactions and the properties of the bulk medium. Intermolecular interactions are sensitive to solvation equilibria, so molecular recognition probes provide fundamentally different information from spectroscopic probes that are sensitive to the populations of different solvation states of the solute. Studies of mixed solvents demonstrate the potential of molecular recognition probes for providing new insights into solvation phenomena.     

Dynamics of protein and peptide hydration

Biological processes often involve the surfaces of proteins, where the structural and dynamic properties of the aqueous solvent are modified. Information about the dynamics of protein hydration can be obtained by measuring the magnetic relaxation dispersion (MRD) of the water (2)H and (17)O nuclei or by recording the nuclear Overhauser effect (NOE) between water and protein protons. Here, we use the MRD method to study the hydration of the cyclic peptide oxytocin and the globular protein BPTI in deeply supercooled solutions. The results provide a detailed characterization of water dynamics in the hydration layer at the surface of these biomolecules. More than 95% of the water molecules in contact with the biomolecular surface are found to be no more than two-fold motionally retarded as compared to bulk water. In contrast to small nonpolar molecules, the retardation factor for BPTI showed little or no temperature dependence, suggesting that the exposed nonpolar residues do not induce clathrate-like hydrophobic hydration structures. New NOE data for oxytocin and published NOE data for BPTI were analyzed, and a mutually consistent interpretation of MRD and NOE results was achieved with the aid of a new theory of intermolecular dipolar relaxation that accounts explicitly for the dynamic perturbation at the biomolecular surface. The analysis indicates that water-protein NOEs are dominated by long-range dipolar couplings to bulk water, unless the monitored protein proton is near a partly or fully buried hydration site where the water molecule has a long residence time.     

Structural ordering and spectral properties of smectic A with biaxial solute molecules

The influence of (i) orientational-translational ordering of solvent and solute molecules, (ii) anisotropic intermolecular solute-solvent interactions and (iii) the features of the electronic structure of biaxial solute molecules dissolved in a smectic A phase on the spectral position of polarized bands of a solute electronic absorption has been investigated. Equations for the positional-orientational pseudopotential in a pure smectic A doped with biaxial solute molecules have been obtained within the framework of the molecular statistical approach. The question about the correlation of contributions of partial orientational and translational molecular ordering to the spectral properties of a molecular system has been answered.     

Why ionic liquids can possess extra solvent power

We use the Flory-Huggins theory to demonstrate conditions of extra solvent power of ionic liquids. The short-range interactions between anions, cations, and molecules of the solute are taken into account. We find that solvent power of the ionic liquids is enhanced if non-Coulomb interactions between the anions and cations are repulsive. The mechanism responsible for the extra solvent power is related to the "shielding" of the anion-cation interactions by the molecules of the solute.     

Solute-solvent intermolecular vibronic coupling as manifested by the molecular near-field effect in resonance hyper-Raman scattering

Vibronic coupling within the excited electronic manifold of the solute all-trans-β-carotene through the vibrational motions of the solvent cyclohexane is shown to manifest as the "molecular near-field effect," in which the solvent hyper-Raman bands are subject to marked intensity enhancements under the presence of all-trans-β-carotene. The resonance hyper-Raman excitation profiles of the enhanced solvent bands exhibit similar peaks to those of the solute bands in the wavenumber region of 21,700-25,000 cm(-1) (10,850-12,500 cm(-1) in the hyper-Raman exciting wavenumber), where the solute all-trans-β-carotene shows a strong absorption assigned to the 1A(g) → 1B(u) transition. This fact indicates that the solvent hyper-Raman bands gain their intensities through resonances with the electronic states of the solute. The observed excitation profiles are quantitatively analyzed and are successfully accounted for by an extended vibronic theory of resonance hyper-Raman scattering that incorporates the vibronic coupling within the excited electronic manifold of all-trans-β-carotene through the vibrational motions of cyclohexane. It is shown that the major resonance arises from the B-term (vibronic) coupling between the first excited vibrational level (v = 1) of the 1B(u) state and the ground vibrational level (v = 0) of a nearby A(g) state through ungerade vibrational modes of both the solute and the solvent molecules. The inversion symmetry of the solute all-trans-β-carotene is preserved, suggesting the weak perturbative nature of the solute-solvent interaction in the molecular near-field effect. The present study introduces a new concept, "intermolecular vibronic coupling," which may provide an experimentally accessible∕theoretically tractable model for understanding weak solute-solvent interactions in liquid.     

Electron transfer in a radical ion pair: quantum calculations of the solvent reorganization energy

Results are presented for an investigation of intermolecular electron transfer (ET) in solution by means of quantum calculations. The two molecules that are involved in the ET reaction form a solvent-separated radical ion pair. The solvent plays an important role in the ET between the two molecules. In particular, it can give rise to specific solute-solvent interactions with the solutes. An example of specific interactions is the formation of a hydrogen bond between a protic solvent and one of the molecules involved in the ET. We address the study of this system by means of quantum calculations on the solutes immersed in a continuum solvent. However, when the solvent can give rise to hydrogen bond formation with the negatively charged ion after ET, we explicitly consider solvent molecules in the solute cavity, determining the hydrogen bond energetic contribution to the overall interaction energy. Solute-solvent pair distribution functions, showing the different arrangement of solvent molecules before and after ET in the first solvation shell, are reported. We provide results of the solvent reorganization energy from quantum calculations for both the two isolated fragments and the ion pair in solution. Results are in agreement with available experimental data.     

Amino acid side chain interactions in the presence of salts

The effects of salt on the intermolecular interactions between polar/charged amino acids are investigated through molecular dynamics simulations. The mean forces and associated potentials are calculated for NaCl salt in the 0-2 M concentration range at 298 K. It is found that the addition of salt may stabilize or destabilize the interactions, depending on the nature of the interacting molecules. The degree of (de)stabilization is quantified, and the origin of the salt-dependent modulation is discussed based upon an analysis of solvent density profiles. To gain insight into the molecular origin of the salt modulation, spatial distribution functions (sdf's) are calculated, revealing a high degree of solvent structuredness in all cases. The peaks in the sdf's are consistent with long-range hydrogen-bonding networks connecting the solute hydrophilic groups, and that contribute to their intermolecular solvent-induced forces. The restructuring of water around the solutes as they dissociate from close contact is analyzed. This analysis offers clues on how the solvent structure modulates the effective intermolecular interactions in complex solutes. This modulation results from a critical balance between bulk electrostatic forces and those exerted by (i) the water molecules in the structured region between the monomers, which is disrupted by ions that transiently enter the hydration shells, and (ii) the ions in the hydration shells in direct interactions with the solutes. The implications of these findings in protein/ligand (noncovalent) association/dissociation mechanisms are briefly discussed.     

Observation of intermolecular interactions in large protein complexes by 2D-double difference nuclear Overhauser enhancement spectroscopy: application to the 44 kDa interferon-receptor complex

NMR detection of intermolecular interactions between protons in large protein complexes is very challenging because it is difficult to distinguish between weak NOEs from intermolecular interactions and the much larger number of strong intramolecular NOEs. This challenging task is exacerbated by the decrease in signal-to-noise ratio in the often used isotope-edited and isotope-filtered experiments as a result of enhanced T(2) relaxation. Here, we calculate a double difference spectrum that shows exclusively intermolecular NOEs and manifests the good signal-to-noise ratio in 2D homonuclear NOESY spectra even for large proteins. The method is straightforward and results in a complete picture of all intermolecular interactions involving non exchangeable protons. Ninety-seven such (1)H-(1)H NOEs were assigned for the 44 KDa interferon-α2/IFNAR2 complex and used for docking these two proteins. The symmetry of the difference spectrum, its superb resolution, and unprecedented signal-to-noise ratio in this large protein/receptor complex suggest that this method is generally applicable to study large biopolymeric complexes.     

X-Ray Studies of 2-Methyl-2-Propanol Solution in Cyclohexane

Abstract

Changes in the mean least intermolecular distances in a solution of 2-methyl-2-propanol in cyclohexane with increasing concentration of the former were found to be non-linear. Both in the range of low (0.005–0.04 molar fraction) and high (0.45–0.75 molar fraction) concentrations of the solutions studied local maxima of the mean least intermolecular distance were observed. In the range from 0.8 to 1 molar fraction the value of this parameter remained constant. Results obtained in this work prove the absence of the specific structural properties of a low concentration alcohol solution observed in other solvents. The occurrence of the local maxima proves that cyclohexane is a non-active solvent. Owing to this the molecules of the solute and the solvent assume positions ensuring homogeneity of the solvents.     

Hybrid Monte Carlo simulations of vertical electronic transitions in acetone in aqueous solution

A simulation of the absorption and the fluorescence of acetone in aqueous solution is reported. The model has an explicit solvent representation with an effective ab initio treatment of the solute. The model attempts to balance quantum chemistry, intermolecular interactions and statistical thermodynamics. It includes a non-electrostatic perturbation on the solute which models the solute–solvent exchange repulsion and the restriction put on the electronic structure of the solute by the antisymmetry to the solvent. The solvent shift to the absorption transition is found to be between 0.16 and 0.21 eV; the shift to the fluorescence transition is found to be between 0.02 and 0.05 eV. The simulation supports the conclusion that the first peak in the fluorescence spectrum of acetone is from a single molecule in equilibrium with the solvent, not from an excimer.     

Interpreting NMR data for beta-peptides using molecular dynamics simulations

NMR is one of the most used techniques to resolve structure of proteins and peptides in solution. However, inconsistencies may occur due to the fact that a polypeptide may adopt more than one conformation. Since the NOE distance bounds and (3)J-values used in such structure determination represent a nonlinear average over the total ensemble of conformers, imposition of NOE or (3)J-value restraints to obtain one unique conformation is not an appropriate procedure in such cases. Here, we show that unrestrained MD simulation of a solute in solution using a high-quality force field yields a conformational ensemble that is largely compatible with the experimental NMR data on the solute. Four 100 ns MD simulations of two forms of a nine-residue beta-peptide in methanol at two temperatures produced conformational ensembles that were used to interpret the NMR data on this molecule and resolve inconsistencies between the experimental NOEs. The protected and unprotected forms of the beta-peptide adopt predominantly a 12/10-helix in agreement with the qualitative interpretation of the NMR data. However, a particular NOE was not compatible with this helix indicating the presence of other conformations. The simulations showed that 3(14)()-helical structures were present in the ensemble of the unprotected form and that their presence correlates with the fulfillment of the particular NOE. Additionally, all inter-hydrogen distances were calculated to compare NOEs predicted by the simulations to the ones observed experimentally. The MD conformational ensembles allowed for a detailed and consistent interpretation of the experimental data and showed the small but specific conformational differences between the protected and unprotected forms of the peptide.