Nonzwitterionic Forms Research Articles

Hydration Effect on Positron Binding Ability of Proline: Positron Attachment Induces Proton-Transfer To Form Zwitterionic Structure.

The positron binding abilities of proline and its hydrated clusters were theoretically studied using multicomponent molecular orbital (MC_MO) calculations. Low-lying equilibrium structures of the neutral proline·(H2O) n ( n = 0-2) clusters were systematically explored with the aid of global reaction route mapping code. The positron binding energies were then calculated for the equilibrium structures. We found that the zwitterionic forms generally displayed high positron binding energies owing to their highly polar nature. We also found that nonzwitterionic forms can exhibit high positron binding energies if the addition of water significantly increases the total electric dipole moment. These results demonstrate that the most stable positron-bound proline·(H2O) n ( n = 1 and 2) structures are more stable than the most stable neutral structures, which implies that the attachment of a positron to a neutral hydrated proline cluster can induce structural changes if the positron-electron annihilation lifetime is sufficiently long relative to the time scale of nuclear motion. We also examined the influence of positron binding on the energy profiles of the proton transfer reactions from the nonzwitterionic form to the zwitterionic form.

Ten-membered rings as key interaction motifs in folding of desmuramyl di-, tri-, and tetrapeptides

Muropeptides are fragments of polymeric peptidoglycan, unique constituent of bacterial cell walls, acting as immunostimulators (adjuvants). The smallest biologically active unit of peptidoglycan is N-acetylmuramyl-L-alanyl-D-isoglutamine. In this paper, the synthesis and conformational analysis of desmuramyl peptides, derivatives lacking the N-acetylmuramyl moiety, is described. Systematic conformational analysis (bottom-up approach) of peptides in zwitterionic and non-zwitterionic forms of corresponding desmuramyl di-, tri-, and tetrapeptides was performed and results were compared with experimental data obtained by NMR study. Ten-membered ring (C10, N1bH⋯O3) formed between isoGln amide group and C=O of AdGly was found to be a key interaction that constitutes the central structural spine and initiates β-turn-like folding in our model peptide systems.

Hydrogen bond mediated stabilization of the salt bridge structure for the glycine dimer anion.

The formation of a salt bridge in deprotonated glycine dimer anions in a solvent-free environment is investigated using both infrared multiple photon dissociation spectroscopy between 600 and 1800 cm(-1) and theory. The zwitterionic and nonzwitterionic forms of glycine in this complex are computed to be nearly iso-energetic, yet predominantly the zwitterionic form is observed experimentally. The zwitterion stability is attributed to both the Coulombic attraction and the high stabilization from intramolecular hydrogen bonding that drives the energetic cost of proton transfer in a solvent free environment. These results show that there is a fine balance between the stabilities of these two forms of the anion. Elucidating the role of intrinsic factors, such as hydrogen bonding, can lead to a better understanding of the stabilities of salt bridges in the interiors of large proteins or at protein interfaces.

Conformational Preferences of Hypermodified Nucleoside Lysidine (k2C) Occurring at “Wobble” Position in Anticodon Loop of tRNAIle

Conformational preferences of hypermodified nucleoside, 4-amino-2-(N6-lysino)-1-(β-D-ribofuranosyl) pyrimidinium (Lysidine or 2-lysyl cytidine), usually designated as k2C, have been investigated theoretically by the quantum chemical perturbative configuration interaction with localized orbitals (PCILO) method. The zwitterionic, non-zwitterionic, neutral, and tautomeric forms have been studied. Automated geometry optimization using molecular mechanics force field (MMFF), semi-empirical quantum chemical PM3, and ab initio molecular orbital Hartree-Fock SCF quantum mechanical calculations have also been made to compare the salient features. The predicted most stable conformations of zwitterionic, non-zwitterionic, neutral, and tautomeric form are such that in each of these molecules the orientation of lysidine moiety (R) is trans to the N(1) of cytidine. The preferred base orientation is anti (χ = 3°) and the lysine substituent folds back toward the ribose ring. This results in hydrogen bonding between the carboxyl oxygen O(12a) of lysine moiety and the 2′-hydroxyl group of ribose sugar. In all these four forms of lysidine O(12a)…H-C(9) and O(12b)…H-N(11) interactions provide stability to respective stable conformers. Watson-Crick base pairing of lysidine with A is feasible only with the tautomeric form of usual anti oriented lysidine. This can help in recognition of AUA codon besides in avoiding misrecognition of AUG.

Alkali Metal Ion Binding to Glutamine and Glutamine Derivatives Investigated by Infrared Action Spectroscopy and Theory

The gas-phase structures of alkali-metal cationized glutamine are investigated by using both infrared multiple photon dissociation (IRMPD) action spectroscopy, utilizing light generated by a free electron laser, and theory. The IRMPD spectra contain many similarities that are most consistent with glutamine adopting nonzwitterionic forms in all ions, but differences in the spectra indicate that the specific nonzwitterionic forms adopted depend on metal-ion identity. For ions containing small alkali metals, the metal ion is solvated predominantly by the amino group, the carbonyl oxygen of the carboxylic acid group, and the carbonyl oxygen of the amide group. With increasing alkali-metal-ion size, additional structures are present in which the carboxylic acid group donates a hydrogen bond to the amino group and the metal ion is solvated only by the amide and carboxylic acid groups. The effects of alkylation of the amino and amide groups on the proton affinity of isolated glutamine and the relative zwitterion stability of sodiated glutamine were examined computationally. Methylation of the amino group increases the proton affinity of isolated glutamine and preferentially stabilizes the zwitterionic form of sodiated glutamine by roughly 20 kJ/mol. Ethylation and isopropylation of the amide group each increase the proton affinity of isolated glutamine by roughly 13 kJ/mol but preferentially stabilize the zwitterionic form of sodiated glutamine by less than 3 kJ/mol. These results indicate that effects of proton affinity on relative zwitterion stability compete with effects of metal-ion solvation.

Effects of Alkaline Earth Metal Ion Complexation on Amino Acid Zwitterion Stability: Results from Infrared Action Spectroscopy

The structures of isolated alkaline earth metal cationized amino acids are investigated using infrared multiple photon dissociation (IRMPD) spectroscopy and theory. These results indicate that arginine, glutamine, proline, serine, and valine all adopt zwitterionic structures when complexed with divalent barium. The IRMPD spectra for these ions exhibit bands assigned to carboxylate stretching modes, spectral signatures for zwitterionic amino acids, and lack bands attributable to the carbonyl stretch of a carboxylic acid functional group. Structural and spectral assignments are strengthened through comparisons with absorbance spectra calculated for low-energy structures and the IRMPD spectra of analogous ions containing monovalent alkali metals. Many bands are significantly red-shifted from the corresponding bands for amino acids complexed with monovalent metal ions, owing to increased charge transfer to divalent metal ions. The IRMPD spectra of arginine complexed with divalent strontium and barium are very similar and indicate that arginine adopts a zwitterionic form in both ions. Calculations indicate that nonzwitterionic forms of arginine are lowest in free energy in complexes with smaller alkaline earth metal cations and that zwitterionic forms are preferentially stabilized with increasing metal ion size. B3LYP and MP2 calculations indicate that zwitterionic forms of arginine are lowest in free energy for M = Ca, Sr, and Ba.

Infrared Spectroscopy of Cationized Arginine in the Gas Phase: Direct Evidence for the Transition from Nonzwitterionic to Zwitterionic Structure

The gas-phase structures of protonated and alkali metal cationized arginine (Arg) and arginine methyl ester (ArgOMe) are investigated with infrared spectroscopy and ab initio calculations. Infrared spectra, measured in the hydrogen-stretch region, provide compelling evidence that arginine changes from its nonzwitterionic to zwitterionic form with increasing metal ion size, with the transition in structure occurring between lithium and sodium. For sodiated arginine, evidence for both forms is obtained from spectral deconvolution, although the zwitterionic form is predominant. Comparisons of the photodissociation spectra with spectra calculated for low-energy candidate structures provide additional insights into the detailed structures of these ions. Arg*Li+, ArgOMe*Li+, and ArgOMe*Na+ exist in nonzwitterionic forms in which the metal ion is tricoordinated with the amino acid, whereas Arg*Na+ and Arg*K+ predominately exist in a zwitterionic form where the protonated side chain donates one hydrogen bond to the N terminus of the amino acid and the metal ion is bicoordinated with the carboxylate group. Arg*H+ and ArgOMe*H+ have protonated side chains that form the same interaction with the N terminus as zwitterionic, alkali metal cationized arginine, yet both are unambiguously determined to be nonzwitterionic. Calculations indicate that for clusters with protonated side chains, structures with two strong hydrogen bonds are lowest in energy, in disagreement with these experimental results. This study provides new detailed structural assignments and interpretations of previously observed fragmentation patterns for these ions.

Non‐zwitterionic structures of aliphatic‐only peptides mediated the formation and dissociation of gas phase radical cations

We have investigated how the non-zwitterionic and zwitterionic structures of aliphatic-only tripeptides affect the formation and dissociation of peptide radical cations in the gas phase. The non-zwitterionic forms of the aliphatic-only peptides in their metal complexes play an important role in determining whether the electron transfer pathway predominates. We extended this study by synthesizing permanent non-zwitterionic and zwitterionic forms of aliphatic-only peptide radical cations and exploring their reactivities in the gas phase. Collision-induced dissociation spectra demonstrated the feasibility of generating both non-zwitterionic and zwitterionic forms. Radical cations in zwitterionic forms may indeed mediate the beta and gamma carbon-carbon bond cleavages of leucine and isoleucine side chains from the GlyGlyXle radical peptides; this feature allows leucine and isoleucine residues to be distinguished unambiguously.

Structures of Lithiated Lysine and Structural Analogues in the Gas Phase: Effects of Water and Proton Affinity on Zwitterionic Stability

The structures of lithiated lysine, ornithine, and related molecules, both with and without a water molecule, are investigated using both density functional theory and blackbody infrared radiative dissociation experiments. The lowest-energy structure of lithiated lysine without a water molecule is nonzwitterionic; the metal ion interacts with both nitrogen atoms and the carbonyl oxygen. Structures in which lysine is zwitterionic are higher in energy by more than 29 kJ/mol. In contrast, the singly hydrated clusters with the zwitterionic and nonzwitterionic forms of lysine are more similar in energy, with the nonzwitterionic form more stable by only approximately 7 kJ/mol. Thus, a single water molecule can substantially stabilize the zwitterionic form of an amino acid. Analogous molecules that have methyl groups attached to either the N-terminus (NMeLys) or the side-chain amine (Lys(Me)) have proton affinities greater than that of lysine. In the lithiated clusters with a water molecule attached, the zwitterionic forms of NMeLys and Lys(Me) are calculated to be approximately 4 and approximately 11 kJ/mol more stable than the nonzwitterionic forms, respectively. Calculations of the potential-energy pathway for interconversion between the different forms of lysine in the lithiated complex indicate multiple stable intermediates with an overall barrier height of approximately 83 kJ/mol between the lowest-energy nonzwitterionic form and the most accessible zwitterionic form. Experimentally determined binding energies of water are similar for all these complexes and range from 57 to 64 kJ/mol. These results suggest that loss of a water molecule from the lysine complexes is both energetically and entropically favored compared to interconversion between the nonzwitterionic and zwitterionic structures. Comparisons to calculated binding energies of water to the various structures show that the experimental results are most consistent with the nonzwitterionic forms.

Experimental/Theoretical Electrostatic Properties of a Styrylquinoline-Type HIV-1 Integrase Inhibitor and Its Progenitors

We have established that polyhydroxylated styrylquinolines are potent inhibitors of HIV-1 integrase (IN). Among them, we have identified (E)-8-hydroxy-2-[2-(4,5-dihydroxy-3-methoxyphenyl)-ethenyl]-7-quinolinecarboxylic acid (1) as a promising lead. Previous molecular dynamics simulations and docking procedures have shown that the inhibitory activity involves one or two metal cations (Mg2+), which are present in the vicinity of the active center of the enzyme. However, such methods are generally based on a force-field approach and still remain not as reliable as ab initio calculations with extended basis sets on the whole system. To go further in this area, the aim of the present study was to evaluate the predictive ability of the electron density and electrostatic properties in the structure-activity relationships of this class of HIV-1 antiviral drugs. The electron properties of the two chemical progenitors of 1 were derived from both high-resolution X-ray diffraction experiments and ab initio calculations. The twinning phenomenon and solvent disorder were observed during the crystal structure determination of 1. Molecule 1 exhibits a planar s-trans conformation, and a zwitterionic form in the crystalline state is obtained. This geometry was used for ab initio calculations, which were performed to characterize the electronic properties of 1. The electron densities, electrostatic potentials, and atomic charges of 1 and its progenitors are here compared and analyzed. The experimental and theoretical deformation density bond peaks are very comparable for the two progenitors. However, the experimental electrostatic potential is strongly affected by the crystal field and cannot straightforwardly be used as a predictive index. The weak difference in the theoretical electron densities between 1 and its progenitors reveals that each component of 1 conserves its intrinsic properties, an assumption reinforced by a 13C NMR study. This is also shown through an excellent correlation of the atomic charges for the common fragments. The electrostatic potential minima in zwitterionic and nonzwitterionic forms of 1 are discussed in relation with the localization of possible metal chelation sites.

Structures of Cationized Proline Analogues: Evidence for the Zwitterionic Form

The structures of lithiated and sodiated alpha-methyl-proline (alpha-Me-Pro) and structural isomers, both with and without a water molecule, are investigated using blackbody infrared radiative dissociation (BIRD) and density functional theory. From the BIRD kinetic data measured as a function of temperature, combined with master equation modeling of these data, threshold dissociation energies for the loss of a water molecule from these clusters are obtained. These energies are 77.5 +/- 0.5 and 53 +/- 1 kJ/mol for lithiated and sodiated alpha-Me-Pro, respectively. For the nonzwitterionic isomer, proline methyl ester, these values are 3.0-4.5 kJ/mol higher. These results provide compelling experimental evidence that alpha-Me-Pro is zwitterionic in these clusters. Theory at the temperature corrected B3LYP/6-311++G**//B3LYP/6-31++G** level indicates that the salt-bridge or zwitterionic forms of lithiated and sodiated alpha-Me-Pro are between 17 and 23 kJ/mol lower in energy than the nonzwitterionic or charge-solvated forms and that attachment of a single water molecule does not significantly change the structure or the relative energies of these clusters. The proton affinity of proline is 8 kJ/mol higher than that of alpha-Me-Pro, indicating that lithiated and sodiated singly hydrated proline should also be zwitterionic.

Sequential bond energies of water to sodium glycine cation

Absolute bond dissociation energies of water to sodium glycine cations and glycine to hydrated sodium cations are determined experimentally by competitive collision-induced dissociation (CID) of Na +Gly(H 2O) x , x = 1–4, with xenon in a guided ion beam tandem mass spectrometer. The cross sections for CID are analyzed to account for unimolecular decay rates, internal energy of reactant ions, multiple ion–molecule collisions, and competition between reaction channels. Experimental results show that the binding energies of water and glycine to the complexes decrease monotonically with increasing number of water molecules. Ab initio calculations at four different levels show good agreement with the experimental bond energies of water to Na +Gly(H 2O) x , x = 0–3, and glycine to Na +(H 2O), whereas the bond energies of glycine to Na +(H 2O) x , x = 2–4, are systematically higher than the experimental values. These discrepancies may provide some evidence that these Na +Gly(H 2O) x complexes are trapped in excited state conformers. Both experimental and theoretical results indicate that the sodiated glycine complexes are in their nonzwitterionic forms when solvated by up to four water molecules. The primary binding site for Na + changes from chelation at the amino nitrogen and carbonyl oxygen of glycine for x = 0 and 1 to binding at the C terminus of glycine for x = 2–4. The present characterization of the structures upon sequential hydration indicates that the stability of the zwitterionic form of amino acids in solution is a consequence of being able to solvate all charge centers.

A hybrid quantum mechanical molecular mechanical method: Application to hydration free energy calculations

A hybrid quantum mechanical molecular mechanical (QMMM) approach is used to study H3O+, H2O, NH4+, NH3, Cl−, HCl, F−, HF, CH3COO−, CH3COOH, Ag+ and glycine in both zwitterionic and nonzwitterionic forms in water. The free energies of hydration of these species are presented and are shown to compare favorably with experimental values. The difference in water–glycine interaction energy between the zwitterionic and nonzwitterionic forms is calculated as a lower limit and is in line with previous findings. The first theoretical examination of the Ag+–glycine complex in solution is presented.

Quantum-chemical gas-phase calculations on the protonation forms oftrans- andcis-urocanic acid

The neutral, cationic, and anionic structures of both prototropic tautomers oftrans- andcis-urocanic acid [(E)- and (Z)-3-(1′H-imidazol-4′(5′)-yl)propenoic acid, respectively] were studied by using semiempirical andab initio gas-phase calculations. Potential energy surfaces of the structures were calculated by using the semiempirical AM1 method, and the geometries corresponding to global minima on these surfaces were optimized up to the MP2/6-31G* level of theory. The calculated protonation forms of each urocanic acid isomer have a planar molecular structure due to a delocalized π-electron system, and all of them prefer thes-trans conformation with respect to the bond between the imidazole and the propenoic acid moieties. Thecis-urocanic acid structures are stabilized by an intramolecular hydrogen bond. The chargedcis-urocanic acid isomers have a lower molecular energy than the correspondingtrans-isomers, whereas the neutral molecules have, after inclusion of thermodynamic corrections, approximately the same energy. The cationic urocanic acid structures have about 2500 kJ mol−1 lower energy than the anionic ones and about 1000 kJ mol−1 lower energy than the neutral ones. The nonzwitterionic forms of the neutral urocanic acid isomers have about 200 kJ mol−1 lower energy than the zwitterionic ones. These energy differences are explained by the proton affinities of the imidazole and the propenoic acid moieties of the urocanic acid structures.

Proton transfer and triol formation in the simulation ofGABA solvation

γ-Aminobutyric acid (GABA) is an inhibitory transmitter used by interneurons in the central nervous system (CNS). In aqueous solution GABA exists as a zwitterion, but in the gas phase the stable form of GABA is a nonzwitterion. Since zwitterions are difficult to transport into the CNS, details of the mechanism for the transformation between nonzwitterionic and zwitterion forms of GABA provide potentially important suggestions for enhancing transport of GABA and GABA analogues into the CNS. A mechanism for the conversion of GABA into the zwitterion form upon aqueous solvation is suggested as a multistage process by simple quantum chemical simulation. Initially, hydrogen bonding at the carbonyl oxygen is followed by attack of water at the carbonyl carbon and results in the formation of a triol. Hydrogen bond bridging, through solvent, from the triol end of the molecule to the amino terminus, facilitates N-protonation from the solvent. The latter appears to trigger rearrangement of the hydrogen bonding at the triol function, thus giving the anionic precursor to the zwitterion. This mechanism is based upon full INDO calculations using a supermolecule composed of GABA and 14 water molecules and resembles part of one of the mechanisms for the hydrolysis of esters as well as a process for the hydration of aldehydes.

Molecular Conformations of γ-Aminobutyric Acid and γ-Amino-β-hydroxybutyric Acid in Aqueous Solution

Abstract Proton magnetic resonance and Raman spectra indicate that the backbone of γ-aminobutyric acid is fairly flexible and rotational isomers are almost equally populated in aqueous solution. The population is not much affected by change of pH. On the other hand, in γ-amino-β-Hydroxybutyric acid the trans-trans and gauche-trans conformations of the backbone are equally populated in neutral solution, trans-trans conformation being predominant in non-zwitterionic forms. The conformation in solution is discussed in relation to the structure of these molecules in crystal.