Understanding enzymic catalysis: the importance of short,strong hydrogen bonds

We have proposed previously that short, strong hydrogen bonds exist in enzyme active sites and that they are important in explaining enzymic rate enhancements. Here, we defend this proposal and provide evidence for likely changes of hydrogen bond strengths during enzymic catalysis.     

Computational evidence for methyl-donated hydrogen bonds and hydrogen-bond networking in 1,2-ethanediol-dimethyl sulfoxide

The 1:1 complex of 1,2-ethanediol with dimethyl sulfoxide was studied using density functional theory. A network of three hydrogen bonds holds the complex together, including two in which each methyl group donates to the same hydroxyl oxygen. Four lines of evidence support the existence of methyl-donated hydrogen bonds. The interaction energy is 36 +/- 5 kJ/mol using Becke's three parameter hybrid theory with the 1991 nonlocal correlation functional of Perdew and Wang, and a moderately large basis set (B3PW91/6-311++G**//B3PW91/6-31+G**). To determine the energy of each hydrogen bond, a relaxed potential energy scan was performed in a smaller basis set to break the weaker hydrogen bonds by forced systematic rotation of the methyl groups. Two cross-checking analyses show cooperative effects that cause individual hydrogen bond energies in the network to be nonadditive. When one methyl hydrogen bond is broken, the remaining interactions stabilize the complex by storing an additional 2-3 kJ/mol. With all hydrogen bonds intact, the O[bond]H...O[bond]S hydrogen bond contributes 26 +/- 2 kJ/mol stability, and each weak methyl bond stores 5 +/- 2 kJ/mol.     

Metal coordination and imine-amine hydrogen bonding as the source of strongly shifted adenine pKa values

The X-ray crystal structure of a Pt(II) complex of composition trans-[(NH(3))(2)Pt(1,9-DimeA) (1,9-DimeAH)](ClO(4))(3) (2) with 1,9-DimeA = 1,9-dimethyladenine and 1,9-DimeAH(+) = 1,9-dimethyladeninium) is presented. Complex 2 forms upon deprotonation of one of the exocyclic amino groups of the adeninium ligands in trans-[(NH(3))(2)Pt(1,9-DimeAH)(2)](ClO(4))(4) (1), where the two nucleobases are in a head-tail arrangement. The low pK(a1) of 1 (4.1 +/- 0.2) is a consequence of a combination of the effects of metal coordination to N7 of the purine base and efficient stabilization of the deprotonated species. This feature is supported by the results of the structure determination of 2, which displays a head-head orientation of the two bases and intramolecular H-bonding between the imine group of 1,9-DimeA and the amino group of 1,9-DimeAH. In the fully deprotonated species trans-[(NH(3))(2)Pt(1,9-DimeA)(2)](ClO(4))(2) (3), the two nucleobases are again in a head-tail arrangement. The findings are of relevance with regard to the concept of "shifted pK(a) values" of nucleobases. This concept is applied to rationalize acid-base catalysis reactions involving nucleobases of DNA and RNA which occur in the near-physiological pH range.     

Determination of pKa values by liquid chromatography

In this paper, we investigate the potential of a high-performance liquid chromatography technique to determine pKa values of drug candidates that show poor solubility in water. The determination of pKa values by this method is in principle not new, but it exhibits simplicity, requires lower quantities of drugs and solvents, and minimal analysis time. The method is an alternative to existing methodology, in which this determination is not readily feasible.     

Effect of hydrogen bonds on orientational order in liquid-crystalline polymers

The orientational behavior of nematic LC copolymers (4-{[6-(acryloyloxy)hexanoyl]oxy}phenyl-4-propoxybenzoate)-co-(4-(6-acryloyloxypropyl-1-oxy)benzoic acid) in a magnetic field has been studied by ²H NMR spectroscopy. An increase in the content of carboxyl groups in the copolymer leads to an appreciable growth of the orientational order parameter S _zz .     

NMR determination of pKa values of indoloquinoline alkaloids

Malaria is one of the most serious global health problems. Isolating new therapeutic agents with potential antimalarial activity from natural sources or preparing such agents either semisynthetically or synthetically is one strategy for solving the problem of resistance constantly evolving to the drugs currently in use. For alkaloids, the acid–base dissociation constant, pK_a, is an important characteristic, thought to be associated with biological activity. In this contribution, pK_a values for several indoloquinoline alkaloids were determined by using ¹H NMR spectroscopy in a mixture of solvents. The data were recalculated for water solutions using the correction factors reported previously. The structural dependence of the pK_a values for cryptolepine and its isomers neocryptolepine, isocryptolepine and isoneocryptolepine as well as some substituted neocryptolepine derivatives is discussed. Copyright © 2009 John Wiley & Sons, Ltd.     

Partial hydrogen bonds: structural studies on thioureidoalkylphosphonates

X-ray crystal and molecular structures of the following compounds are investigated: diphenyl 1-(3-phenylthioureido)propylphosphonate (I), diphenyl 1-(3-phenylthioureido)methylthio-propylphosphonate (II), and diphenyl [2-methyl-1-(3-methylthioureido)propyl]phosphonate (III). Additionally single point density functional theory calculations at the B3LYP/6-311+G(d) level of theory are performed on dimers whose geometries are taken from the crystal structures. The additional diffuse and polarization components are included on H-atoms which participate in H-bonds. The obtained wave functions are applied later to study theoretical electron densities for these species. Bond critical points are determined for dimers investigated to characterize the nature of interactions, especially bifurcated acceptor hydrogen bonds. The characteristics of bond critical points are investigated in terms of the electron densities and their Laplacians.     

Non-conventional hydrogen bonds: pterins-metal anions

In this paper, we present an analysis of the interaction of metal ions (Cu, Ag and Au) with three different pterins (pterin, isoxanthopterin and sepiapterin) to provide insights concerning the formation of conventional and non-conventional H bonds. Density functional theory calculations were performed in order to reveal the optimized structures of pterin molecules, dimers and tetramers compounds, both with and without metal anions (M). The interaction with small metal clusters (M(3)) is also considered. The formation of different systems is characterized in terms of the structural parameters and hydrogen binding energies (HBE). The HBE values for pterin-M systems presented in this study lie between 22 and 60 kcal mol(-1) and can therefore be classified as strong conventional and strong non-conventional hydrogen bonds. The HBE with small metal clusters (pterin-M(3)) are smaller than the HBE with metal atoms. Vertical electron detachment energies (VEDEs) are also reported in order to analyze the influence of the hydrogen bond on electronic properties. A direct correlation between VEDEs and HBE was found for pterin-M and pterin-M(3) complexes; i.e. as the VEDEs increase, the HBE also augment. The only exception is with Ag(3). The main conclusion derived from this study is that the strong non-conventional hydrogen bonds formed between pterins, dimers and tetramers do not affect the formation of conventional hydrogen bonds between pterins but they do influence the VEDEs.     

Effect of hydrogen bonds on the axial stiffnes of crystalline native cellulose

Previous theoretical calculations of elastic constants for cellulose based on force constants for bond stretching and bending of valence angles have yielded axial stiffness values admittedly too low. The present analysis accounts for a hitherto unexamined geometrical effect associated with deformation of interchain hydrogen bonds. To do this, most primary bond deformations are neglected so the resulting calculation gives an upper bound for the axial stiffness. By using two different sets of hydrogen bond force constants, values of 24.6 and 31.9 × 10¹¹ dyne/cm² were obtained for Young's modulus in the chain direction. These values are very much larger than earlier calculations and experimental determinations from cellulosic fibers, indicating both the importance of the effect considered here and the likelihood of an exact analysis yielding an acceptable result.     

Diazanaphthalenes: A 13C NMR investigation on the site of protonation and pKa values

The pH dependence of the ¹³C chemical shifts (δ) of the diazanaphthalenes has been recorded. From this dependence the pK_a values have been determined using the Henderson-Hasselbach equation. The change in ¹³C chemical shifts under the influence of nitrogen protonation (Δδ) has been predicted using the Δδ values of quinoline and isoquinoline. The correlation between observed and expected Δδ values of the symmetric diazanaphthalenes is very good. Assuming these changes in chemical shifts to be of general validity, the site of protonation in the asymmetric diazanaphthalenes has been determined by comparison of the expected Δδ values for α- and β-nitrogen protonation with the observed ones. The site of protonation for 1,6- and 1,7-naphthyridine is the β-nitrogen atom, whereas for cinnoline both monoprotonated species are present in a significant amount.     

The vibrations of hydrogen bonds

I present recent inelastic incoherent neutron scattering (INS) work involving the study of the H-bond vibrations. These vibrations have spectral consequences which are strongly dependent upon spectroscopic technique, and these will be indicated for IR and Raman, and detailed for INS. The vibrational dynamics of the simple FHF⁻ will be used by way of an example. These INS results demonstrate that the latest generation of neutron spectrometers provides new insights into H-bonding dynamics.     

Relative pKa values from first-principles molecular dynamics: the case of histidine deprotonation

Accurate calculation of pK(a) values and free energies for acid/base reactions in the condensed phase has been a long-standing goal of theoretical chemistry. We present a novel application of the Car-Parrinello molecular dynamics method to the problem of relative pK(a) determination. As a particular example, we focus on the second stage in the dissociation of histidine, a process that holds special importance for biology. Using constrained molecular dynamics, we have analyzed the structural, electronic, and dynamical transformations taking place along a preselected, intuitive reaction coordinate. By integrating the potentials of mean force for the deprotonation of histidine and for a reference reaction, autodissociation of water, we obtain a pK(a) value of 6.8, which appears to be in good agreement with the experimental estimate of 6.1. Detailed analysis was undertaken to determine the value of the constraint, which transformed the N*-H* from a covalent to a hydrogen bond. This helped to identify a number of properties that could be successfully used in monitoring the dissociation process. Additional analysis in terms of electron localization functions provided valuable insight into the nature of the deprotonation reaction.     

Review: Bilirubin pKa studies; new models and theories indicate high pKa values in water,dimethylformamide and DMSO

Background  

Unconjugated bilirubin (UCB) is an unstable substance with very low aqueous solubility. Its aqueous pKa values affect many of its interactions, particularly their pH-dependence. A companion paper shows that only our prior solvent partition studies, leading to pKa values of 8.12 and 8.44, met all essential requirements for valid pKa determinations. Other published values, generally lower, some below 5.0, were shown to be invalid. The present work was designed to derive suitable models for interpreting published data on the pH-dependent binding of UCB with four agents, mentioned below, chosen because they are not, themselves, sensitive to changes in the pH range 4-10, and the data, mainly spectrometric, were of reasonable quality.     

Determination of pKa values of anthraquinone compounds by capillary electrophoresis

In this paper, the dissociation constants (pKa1, pKa2) of five anthraquinones were determined from the relation between the effective mobility at different pH values and the buffer pH value, which was derived from the basic electrophoresis theory and the dissociation equilibrium of a binary acid. In addition, the changes of pKa values of the five compounds were also investigated when organic modifiers were added to the buffer system.     

Revalidation and rationale for high pKa values of unconjugated bilirubin

Background  

Our prior solvent partition analysis, published in 1992, yielded pKa values for unconjugated bilirubin of about 8.1 and 8.4, but these results have been challenged and studies by other methods have suggested pKa values below 5.0.     

A deuterated deep-cavity cavitand confirms the importance of C-H...X-R hydrogen bonds in guest binding

A deuterated cavitand host was examined for its affinity to a series of guests; for halogenated, preorganized guests binding was significantly stronger than the corresponding protium host.     

Effect of the resonance of molecular vibrations on the ir spectra of hydrogen bonds

The effects are considered of the vibrations occurring with the group of atoms peripheral towards the hydrogen bond on the IR spectrum of the model hydrogen bond. It. is shown that the resonance of the v_OHv_CH stretching vibrations in a hydrogen bonded molecule result in the division of the v_OH band into two other bands having different polarizations. The resonance interaction leads to redistribution of the intensity and perturbs the regular Franck—Condon type envelope of the spectrum.     

The effect of entropy on protein hydrogen bonds

Hydrogen bonds are essential elements in protein structure and dynamics. We show that such bonds are strongly dominated by entropic contributions of the environment that can be at least as important as energetic considerations. These contributions are global in that they are not due to the internal degrees of freedom. The molecular dynamics (MD) is carried out as a computer experiment and agrees very well with the known energies of hydrogen bonds, both in water and in the isolated molecule. The entropy in water as a solvent is found to modulate the hydrogen bond breaking and reformation rate by two orders of magnitude, in a negative direction.