Molecular dynamics of hydrogen bonds in protein-D2O: the solvent isotope effect

We suggest that the H-bond in proteins not only mirrors the motion of hydrogen in its own atomistic setting but also finds its origin in the collective environment of the hydrogen bond in a global lattice of surrounding H2O molecules. This water lattice is being perturbed in its optimal entropic configuration by the motion of the H-bond. Furthermore, bonding interaction with the lattice drop the H-bond energy from some 5 kcal/mol for the pure protein in the absence of H2O, to some 1.6 kcal/mol in the presence of the H2O medium. This low value here is determined in a computer experiment involving MD calculations and is a value close to the generally accepted value for biological systems. In accordance with these computer experiments under ambient conditions, the H-bond energy is seriously depressed, hence confirming the subtle effect of the H2O medium directly interacting with the H-bond and permitting a strong fluxional behavior. Furthermore, water produces a very large change in the entropy of activation due to the hydrogen bond breakage, which affects the rate by as much as 2 orders of magnitude. We also observe that there is an entire ensemble of H-bond structures, rather than a single transition state, all of which contribute to this H-bond. Here the model is tested by changing to D2O as the surrounding medium resulting in a substantial solvent isotope effect. This demonstrates the important influence of the environment on the individual hydrogen bond.     

Probing the nature of three-centered hydrogen bonds in minor-groove ligand-DNA interactions: the contribution of fluorine hydrogen bonds to complex stability

Double-stranded DNA sequences have been prepared in which single atoms (the O2-carbonyls of selected thymines) have been replaced by fluorine or methyl. To maintain normal Watson-Crick hydrogen bonding with the complementary purines, these analogue derivatives have been prepared as C-nucleosides. The O2-carbonyls of interest for this study are those involved in a bifurcated (or three-centered) hydrogen bond with the minor groove binding ligand 4',6-diamidino-2-phenylindole (DAPI). TM studies of the duplexes illustrate that the DNA duplexes are destabilized when fluorine or methyl replaces one or both of the minor groove O2-carbonyls, which can in part be explained by changes in minor groove hydration. In the presence of DAPI, most of the duplexes exhibit an increased TM due to the presence of DAPI bound in the minor groove. The extent of helix overstabilization negatively correlates with the presence of one or both methyl groups in the minor groove, suggesting that ligand binding is weakened in the presence of the non-carbonyl functional groups. The presence of single fluorine appears to promote helix stabilization, and native-like stabilization occurs when both fluorines are present. KD values quantitate binding effects between DAPI and the native and analogue sequences. Sequences with one or both methyl groups exhibit very poor binding with DAPI, while those containing a single fluorine behave essentially like native carbonyl-containing sequences. With both fluorines present, KD values were observed to increase by a moderate 3-fold at 100 mM NaCl and somewhat more at 200 mM NaCl. Binding affinities with both methyl groups present were 500-1000-fold weaker than native. The results suggest that organofluorines can function as hydrogen-bond acceptors, at least in the bifurcated interaction that contributes to minor groove binding by DAPI.     

Imino- and aminomethylphenylboronic acids: stabilizing effect of hydrogen bonds

ortho-Iminomethylphenylboronic acids were synthesized from the reaction of 2-formyl–phenylboronic acid with primary aromatic amines. Reduction of these compounds yielded the corresponding aminomethylphenylboronic acids. For both types of the compounds, the crystal structure was determined by single crystal X-ray diffraction method. Hydrogen-bonded dimers with an additional intramolecular B–O–H…N hydrogen bond have been observed. Calculations at MP2/6–31+G** level proved that the most stable form is that with the above-mentioned intramolecular hydrogen bond while the form with dative N→B bond is less favoured. Since the calculated energy difference is small, the competition between possible forms was analyzed in terms of substituent effect stabilization energy (SESE). In the case of p-iminomethylphenylboronic acid, both hydroxyl groups are engaged in intermolecular O–H…O interactions resulting in a supramolecular ribbon motif.     

Using equilibrium isotope effects to detect intramolecular OH/OH hydrogen bonds: structural and solvent effects

A comparative (1)H NMR study of partially deuterated 1,3- and 1,4-diols has demonstrated that intramolecular hydrogen bonds of different geometry can give rise to equilibrium isotope shifts of opposite sign in hydrogen-bond-accepting solvents such as DMSO-d(6), acetone-d(6), and THF-d(8). The sign inversion is interpreted in terms of the ability of solvent molecules to form competitive intermolecular hydrogen bonds with the diol and in terms of the limiting chemical shifts for the interior and exterior hydroxyl groups. Deuterium is shown to prefer the intermolecular solvent hydrogen bond by 10.9 +/- 0.5 cal/mol for 1,4-diol 3 dissolved in DMSO-d(6) at room temperature. Pyridine-d(5) is shown to be capable of amplifying positive (downfield) isotope shifts measured in DMSO-d(6), in some cases by as much as a factor of 3. Its use is demonstrated for the assignment of the syn or anti relative configuration of 2,4-pentanediol and for the amplification of isotope shifts used to detect intramolecular hydrogen bonds in alpha- and beta-cyclodextrin. Studies in apolar solvents such as CD(2)Cl(2) and benzene-d(6) reveal that the isotope shift is negative (upfield) for all hydrogen bond geometries studied. Larger isotope shifts are measured in benzene-d(6), and a rationale for this amplification is presented. The use of apolar solvents is particularly useful for assigning the syn or anti configuration of 2,4-pentanediol.     

Intermolecular vibrations and diffusive orientational dynamics of Cs condensed ring aromatic molecular liquids

The ultrafast dynamics, including the intermolecular vibrations and the diffusive orientational dynamics, of the neat C(s) symmetry condensed ring aromatic molecular liquids benzofuran, 1-fluoronaphtalene, and quinoline were investigated for the first time by means of femtosecond Raman-induced Kerr effect spectroscopy. To understand the features of these C(s) condensed ring aromatic molecular liquids, reference singular aromatic molecular liquids, furan, fluorobenzene, pyridine, and benzene, were also studied. High quality low-frequency Kerr spectra of the aromatic molecular liquids were obtained by Fourier-transform deconvolution analysis of the measured Kerr transients. The Kerr spectra of the C(s) condensed ring aromatic molecular liquids are bimodal, as are those of the reference singular aromatic molecular liquids. The first moment of the intermolecular vibrational spectrum and the peak frequencies of the high- and low-frequency components in the broad spectrum band were compared with their molecular properties such as the rotational constants, molecular weight, and intermolecular (bimolecular) force. The comparisons show that the molecular volume (related to molecular weight and rotational constants) is a dominant property for the characteristic frequency of the entire intermolecular vibrational spectrum. The observed intramolecular vibrational modes in the Kerr spectra of the aromatic molecular liquids were also assigned on the basis of the ab initio quantum chemical calculation results. In their picosecond diffusive orientational dynamics, the slowest relaxation time constant for both the condensed ring and singular aromatic molecular liquids can be accounted for by the simple Stokes-Einstein-Debye hydrodynamic model.     

Axial and equatorial hydrogen bonds: jet-cooled rotational spectrum of the pentamethylene sulfide...hydrogen fluoride complex

Two different axial and equatorial hydrogen-bonded conformers of the complex formed by pentamethylene sulfide and hydrogen fluoride have been generated in a pulsed supersonic expansion and characterised by means of Fourier transform microwave spectroscopy. The ground-state rotational spectra of six isotopomers (C(5)H(10)S...HF, C(5)H(10)S ...DF, C(5)H(10)(34)S ...HF, (13)C(alpha)C(4)H(10)S ...HF, (13)C(beta)C(4)H(10)S...HF and (13)C(gamma)C(4)H(10)S ...HF) have been analysed for both conformers in the frequency range 5.5-18.5 GHz. The rotational parameters were used to derive C(s) structures for the conformers, with hydrogen fluoride pointing to the domain of the nonbonding electron pairs at either the axial or equatorial position of the sulfur atom. The axial form was found to be the more stable, in contrast with the observation for the pentamethylene sulfide...HCl complex. No equatorial-to-axial relaxation was observed when He or Ar were used as the carrier gas. The conformational behaviour is compared with that of related six-membered rings and discussed in terms of the existence of secondary hydrogen bonding between the halogen atom and the nearest H atoms of the methylene groups of the ring. No significant structural distortion of pentamethylene sulfide upon complexation was detected from a comparison with the structure of the isolated monomer. Finally, an ab initio study was carried out to complement the experimental results.     

Theoretical study of some nitriles: Intramolecular hydrogen bonds and anomeric effect

An ab initio study of 3-chloro-, 3-hydroxy-, 3-mercapto-, and 3-amino-propanenitrile and 4-chloro-bu- tanenitrile was carried out at several levels of theory. The calculated stabilities and geometrical trends are interpreted in terms of the effects of intramolecular hydrogen bonds and anomeric interactions, and compared with available experimental data.     

1H NMR studies of solvent and substituent effects on strong intramolecular hydrogen bonds

Chemical shifts of H-bonded protons in tetrabutylammonium hydrogen maleate and 14-substituted picolinic acid N-oxides have been measured in a number of dry solvents, of different activity, in order to distinguish between symmetrical single minimum and asymmetrical hydrogen bonds. In tetrabutylammonium hydrogen maleate the resonance was observed at 20.70 ppm and its was independent of the nature of the solvent used. The chemical shift value of picolinic acid N-oxide varies with the solvent. These observations suggest that the hydrogen bond is symmetrical in tetrabutylammonium hydrogen maleate but that it is asymmetrical in picolinic acid N-oxide. The chemical shifts of substituted picolinic acid N-oxides were correlated with σ_p, σ_m and Δ_pK_a. The substituent and solvent effects are compared and the position of the intramolecular H-bonded protons in picolinic acid N-oxides are estimated and discussed.     

Activation of hydrogen peroxide through hydrogen-bonding interaction with acidic alcohols: epoxidation of alkenes in phenol

[reaction: see text] Electrophilic activation of hydrogen peroxide can be achieved in acidic alcohol solvents without the need for a metal catalyst. This concept is illustrated by the epoxidation of alkenes with H(2)O(2) employing phenol as a solvent. It is proposed that intermolecular hydrogen bonding between H(2)O(2) and phenol activates H(2)O(2) for oxygen-atom transfer. In this interaction, the role of phenol is purely catalytic.     

Intermolecular hydrogen bonds in hetero-complexes of biologically active aromatic ligands: Monte Carlo simulations results

We report results of the Monte Carlo simulations of systems containing heterodimers of biological active ligands and water molecules. The study was designed to identify the possible formation of intermolecular hydrogen bonds in such systems in order to investigate the molecular mechanisms of hetero-association of aromatic ligands in aqueous solution. The geometry optimization and the calculation of the atomic charges of free ligands were carried out at DFT/B3LYP level of theory. Monte Carlo simulations with Metropolis algorithm were used to determine the low energy conformations of heterodimers in water clusters. The analysis of the Monte Carlo simulation results allows us to describe in detail the hydration properties of all investigated heterodimers and to determine the intermolecular hydrogen bonds between the functional donor–acceptor groups for some of hetero-associates under investigation. In the case of heterodimers without intermolecular hydrogen bonds, the additional stabilization of these hetero-complexes can be explained by the formation the water bridges between donor and acceptor groups of the ligands.     

Competition between intramolecular hydrogen bonds and solvation in phosphorylated peptides: simulations with explicit and implicit solvent

The atomic-level mechanisms of protein regulation by post-translational phosphorylation remain poorly understood, except in a few well-studied systems. Molecular mechanics simulations can in principle be used to help understand and predict the effects of protein phosphorylation, but the accuracy of the results will of course depend on the quality of the force field parameters for the phosphorylated residues as well as the quality of the solvent model. The phosphorylated residues typically carry a -2 charge at physiological pH; however, the effects of phosphorylation can sometimes be mimicked by substituting Asp or Glu for the phosphorylated residue. Here we examine the suitability of explicit and implicit solvent models for simulating phospho-serine in both the -1 and -2 charge states. Specifically, we simulate a capped phosphorylated peptide, Ace-Gly-Ser-pSer-Ser-Nme, and compare the results to each other and to experimental observables from an NMR experiment. The first major conclusion is that explicit water models (TIP3P, TIP4P and SPC/E) and a Generalized Born implicit solvent model provide reasonable agreement with the experimental observables, given appropriate partial charges for the phosphate group. The Generalized Born results, however, show greater hydrogen bonding propensity than the explicit solvent results. Distance dependent dielectric treatments perform poorly. The second major conclusion is that many ensemble-averaged properties obtained for the phosphopeptide in the -1 and -2 charge states are strikingly similar; the -1 species has a slightly higher propensity to form internal hydrogen bonds. All of the results can be rationalized by quantifying the strength of the P-O/H-N hydrogen bond, which depends on a sensitive balance between strongly favorable charge/dipole and dipole/dipole interactions and strongly unfavorable desolvation.     

A novel porous supramolecular complex constructed by the co-crystallization of melamine and sulfate via hydrogen bonds and aromatic π-π interaction

Co-crystallization of melamine(MA) and sulfate results in crystalline product [(C₃H₇N₆⁺)₂(SO₄²⁻)] · 2H₂O. The novel supramolecular complex has been characterized by elemental analysis, thermal analysis (TGA and DSC), nuclear magnetic resonance (NMR), and single crystal X-ray diffraction. X-ray crystallographic studies of the complex reveal that the title complex has a 3-D microporous structure which is linked by intense intermolecular hydrogen-bonding interactions (N–H······O, N–H······N, O–H······O) and aromatic π-π interaction, which stabilize the whole crystal framework. The TGA curve shows that the complex is stable up to 500 °C, above which its structure begins to collapse.     

The influence of intramolecular hydrogen bonds on the adsorption properties of aromatic alcohols and thiols

The thermodynamic characteristics of adsorption equilibria of primary aromatic alcohols and thiols on graphitized carbon black at 300 K were determined by the molecular-statistical method. The influence of intramolecular effects under the action of the force field of the sorbent on the conformation of the molecules studied was considered in comparison with n-alkylbenzenes having similar structures. An increase in the chain length by one-CH₂ group was shown to influence the formation of intramolecular H-bonds in alcohol and thiol molecules. In adsorption, a considerable fraction of molecules assumed configurations close to planar. An exception was the nonplanar conformation of the 2-phenylethanol molecule stabilized by the intramolecular H-bond.     

Conformational isomerism of chlorophenylthioureas and intramolecular N---H … Cl hydrogen bonds: IR spectra of N---H stretching vibrations

The vN---H regions of the IR spectra of thioureas with chlorophenyl (ClPh) groups and those with halophenyl groups were measured in dilute CCl₄ solution. The observed vN---H bands were classified into eight groups according to the wavenumbers and the two substituent groups. The suggested conformational states and the formation of intramolecular N---H … Cl hydrogen bonds in these compounds were discussed in comparison with those of the urea analogs. It was found that these thiourea derivatives are more stable in the cis form than the urea analogs and that thioureas with o-ClPh groups form fewer intramolecular N---H … Cl hydrogen bonds than do the urea analogs.     

Effects of pressure and solvent on the diffusion of aromatic compounds through polymers

The diffusion of six azo and five anthraquinone derivatives through nylon 6, poly(ethylene terephthalate) and secondary cellulose acetate films were studied under high hydrostatic pressures of up to 3000 bar and at temperatures 80–130 °C, by analyzing the diffusion profiles yielded in a stacked multiple film, placed in the solution of the diffusant. It was found that the diffusion coefficient,D, of the diffusant decreased with increasing pressure, giving a linear relationship between InD and the pressure, the slope of which gave the activation volume for the diffusion,V . It was revealedV increased linearly with increasing intrinsic molecular volume of the diffusant,V _w , the slopes being different between the azo and the anthraquinone derivatives. The ratio ofV toV _w (V /V _w ) ranged from 0.13 to 0.93, depending in a sensitive manner on the degree of swelling of the polymer matrix which in turn was varied by the solvent. The overall results could be explained in accordance with the formulation,V _{f, local} +V =V _w , whereV _{f, local} represents the free volume contribution. It was proposed thatV _w is increased by solvation when the solvent is good for the diffusant.     

Small ring compounds—XXX : Homolytical aromatic substitution and hydrogen abstraction reaction with cyclopropyl radical

Homolytic aromatic substitution and hydrogen abstraction reactions with cyclopropyl radical were carried out to determine the reactivity and ionic character of cyclopropyl radical by examination of the orientation effect, partial rate factor and influence of substituents. By thermal decomposition of biscyclopropaneformyl peroxide in a series of substituted benzenes, the corresponding cyclopropylated benzene derivatives (the mixture of ortho, meta and para isomers) were obtained in moderate yield. In view of the orientation effect and the partial rate factor, the cyclopropyl radical seems to be fairly free from polar effect, and to resemble the phenyl radical more than the common alkyl radical although the cyclopropyl radical has a slightly higher reactivity than the phenyl radical. The relative reactivity of the 2-phenylcyclopropyl radical in the hydrogen abstraction reaction toward the benzylic position of ring-substituted toluenes gave good Hammett's correlation with the slope of + 0·20 suggesting little ionic character in the transition state. This result was in good agreement with the conclusion obtained from homolytic aromatic substitution reaction and with the chemical reactivity to be expected from the non-planar nearly sp²-hybridized conformation of the cyclopropyl radical.     

Tuning the interaction energy of hydrogen bonds: the effect of the substituent

The effect of the substituent R in the hydrogen bonding properties of FH···FR (R = H, Al, Li, Cl and CCH) complexes has been studied by theoretical calculations. The dependency of the interaction energy with the hydrogen bond distance and R is explained in terms of the topologies of the electron density and the electrostatic potential. A simple model of the hydrogen bond interaction energy, which can be assimilated to an interaction potential, is defined in terms of a stabilizing mutual polarization of the monomers and an overall destabilizing contribution associated with the electron density reorganization when the overlap of the closed shells is large enough. This model shows an excellent agreement with the ab initio interaction energies and is common for all the analyzed complexes. The substituent effect is represented in the model by a single parameter that can be calculated from the electron distribution in the acceptor atom region. The perturbation in the hydrogen bonding interaction induced by the change of R presents a close similarity with that produced by an external electric field of the same order of magnitude than those found in crystalline solids, indicating that both perturbations should play a significant and similar role on the properties of hydrogen bonds in condensed matter.     

Role of hydrogen bonds in protein-DNA recognition: effect of nonplanar amino groups

Amino groups are one of the various types of hydrogen bond donors, abundantly found in protein main chains, protein side chains, and DNA bases. The polar hydrogen atoms of these groups exhibit short ranged, specific, and directional hydrogen bonds, which play a decisive role in the specificity and stability of protein-DNA complexes. To date, planar amino groups are only considered for the analysis of protein-DNA interfacial hydrogen bonds. This assumption regarding hydrogen atom positions possibly failed to establish the expected role of hydrogen bonds in protein-DNA recognition. We have performed ab initio quantum chemical studies on amino acid side chains and DNA bases containing amino groups as well as on specific hydrogen bonded residue pairs selected from high-resolution protein-DNA complex crystal structures. Our results suggest that occurrences of pyramidal amino groups are more probable in comparison with the usually adopted planar geometry. This increases the quality of the existing hydrogen bonds in almost all cases. Further, detailed analysis of protein-DNA interfacial hydrogen bonds in 107 crystal structures using the in-house program "pyrHBfind" indicates that consideration of energetically more preferred nonplanar amino groups improves the geometry of hydrogen bonds and also gives rise to new contacts amounting to nearly 14.5% of the existing interactions. Large improvements have been observed specifically for the amino groups of guanine, which faces the DNA minor groove and thus helps to resolve the problem of insufficient directional contacts observed in many minor groove binding complexes. Apart from guanine, improvement observed for asparagine, glutamine, adenine, or cytosine also indicates that the consideration of nonplanar amino groups leads to a more realistic scenario of hydrogen bonds occurring between protein and DNA residues.