Incremental solvation of nonionized and zwitterionic glycine

Microsolvation and combined microsolvation-continuum approaches are employed in order to examine the structures and relative energies of nonionized (N) and zwitterionic (Z) glycine clusters. Bridging structures are predicted to be the global minima after 3-5 discrete water molecules are included in the calculations. Calculations incorporating electron correlation stabilize the zwitterionic structures by about 7-9 kcal/mol relative to the N structures regardless of the number of discrete water molecules considered. Continuum calculations stabilize the Z structures relative to N structures; this effect decreases as the number of discrete water molecules is increased. Eight water molecules do not appear to fully solvate glycine.     

Hydrogen-bond symmetry in zwitterionic phthalate anions: symmetry breaking by solvation

The cationic nitrogen of zwitterion 1 is located symmetrically with respect to its intramolecular OHO hydrogen bond. Incorporation of one (18)O allows investigation of the H-bond symmetry by the NMR method of isotopic perturbation. In both CD(3)OD and CD(2)Cl(2) equilibrium isotope shifts are detected at the carboxyl and ipso carbons. Therefore, 1 exists as a pair of interconverting tautomers, not as a single symmetric structure with its hydrogen centered between the two oxygens. The H-bond is instantaneously asymmetric, and there is an equilibrium between solvatomers (isomers or stereoisomers that differ in solvation). The broader implications of this result regarding the role of the local environment ("solvation") in breaking symmetry are discussed.     

Linear solvation energy correlation of the solvatochromic response of amino acid functionalized chromophores

Solvatochromism of the long wavelength band in the electronic absorption spectra of N-(4-nitrophenyl)-L-proline, NLP, N-(4-nitrophenyl)-D-proline, NDP, and N-(4-nitro-phenyl)-trans-4-hydroxy-L-proline, NHP, was studied and quantitatively described with Kamlet-Taft solvent polarity parameters. To evaluate the environmental effects for NLP, NDP, and NHP, the UV-vis spectroscopic behavior of these compounds was also investigated as pure crystals, as a guest in 2,6-O-dimethyl-beta-cyclodextrin, and also when adsorbed on Aerosil 300 silica particles from nonhydrogen-bond accepting solvents. Excellent Kamlet-Taft solvatochromic correlations were established for the three compounds in most solvents. Multiparameter correlations show the existence of specific solute-solvent interactions. A strong positive solvatochromic behavior was found for these compounds, indicating that their dipole moments were higher in the excited singlet state than in the ground state.     

Calculation of the free energy of solvation for neutral analogs of amino acid side chains

The ability of the GROMOS96 force field to reproduce partition constants between water and two less polar solvents (cyclohexane and chloroform) for analogs of 18 of the 20 naturally occurring amino acids has been investigated. The estimations of the solvation free energies in water, in cyclohexane solution, and chloroform solution are based on thermodynamic integration free energy calculations using molecular dynamics simulations. The calculations show that while the force field reproduces the experimental solvation free energies of nonpolar analogs with reasonable accuracy the solvation free energies of polar analogs in water are systematically overestimated (too positive). The dependence of the calculated free energies on the atomic partial charges was also studied.     

Vibrational and photoionization spectroscopy of biomolecules: aliphatic amino acid structures

The aliphatic amino acids glycine, valine, leucine, and isoleucine are thermally placed into the gas phase and expanded into a vacuum system for access by time of flight mass spectroscopy and infrared (IR) spectroscopy in the energy range of 2500-4000 cm(-1) (CH, NH, OH, and stretching vibrations). The isolated neutral amino acids are ionized by a single photon of 10.5 eV energy (118 nm), which exceeds by less than 2 eV their reported ionization thresholds. As has been reported for many hydrogen bonded acid-base systems (e.g., water, ammonia, alcohol, acid clusters, and acid molecules), the amino acids undergo a structural rearrangement in the ion state (e.g., in simplest form, a proton transfer) that imparts sufficient excess vibrational energy to the ion to completely fragment it. No parent ions are observed. If the neutral ground state amino acids are exposed to IR radiation prior to ionization, an IR spectrum of the individual isomers for each amino acid can be determined by observation of the ion intensity of the different fragment mass channels. Both the IR spectrum and fragmentation patterns for individual isomers can be qualitatively identified and related to a particular isomer in each instance. Thus, each fragment ion detected presents an IR spectrum of its particular parent amino acid isomer. In some instances, the absorption of IR radiation by the neutral amino acid parent isomer increases a particular fragmentation mass channel intensity, while other fragmentation mass channel intensities decrease. This phenomenon can be rationalized by considering that with added energy in the molecule, the fragmentation channel populations can be modulated by the added vibrational energy in the rearranged ions. This observation also suggests that the IR absorption does not induce isomerization in the ground electronic state of these amino acids. These data are consistent with theoretical predictions for isolated amino acid secondary structures and can be related to previous IR spectra of amino acid conformers.     

Phenylisoserine: a versatile amino acid for the construction of novel beta-peptide structures

The N-Boc O-tert-butyldimethysilyl-substituted hexa-beta-peptide methyl ester 18 was constructed from the O-TBS ether of (-)-(2R, 3S)-phenylisoserine. By NMR, it was determined that this homo beta-peptide adopts a highly stable beta-strand-type secondary structure in chloroform solution, which is stabilized by both hydrophobic interactions involving the OTBS methyl groups of residues i and i + 2, and inter-(five-membered)/intra (six-membered)-residue H-bonding interactions. These interactions are systematically repeated along the peptide chain and, thereby, operate in concert to stabilize the observed conformation of 18.     

Detailed structures and mechanism of polymer solvation

In the present study, we simulated a model system, PE in biphenyl, to gain the insight into the detailed solvation structures and the molecular mechanism of polymer chain solvation. Using atomistic molecular dynamics (MD) simulation, it was found that when the biphenyl is far from PE chain or in the bulk, the dihedral angle of the two rings in the solvent molecule are approximately 32 degrees. But, the dihedral angel is about 27 degrees when the biphenyls are very close to the PE chain. In the first solvation shell, the orientation angle of the biphenyl long axis to the chain segment backbone was found to be enhanced around two values: approximately 0 and approximately 60 degrees. The detailed solvation structures found here include all dyad conformations (TT, TG, TG', GT, GG, GG', G'T, G'G, and G'G') and vary as a function of the distance between PE chain and biphenyls in the first solvation shell. The closer the the solvent molecule to the PE segment, the higher the TT conformation fraction response is. The other dyad conformations such as TG, GG', etc. undergo different decreases, respectively. This study shows that the solvation even in the Theta condition makes the overall size expansion or the chain stretched. Such a cooperative change was examined here and found not due to generating or losing a conformational state but due to a change in conformational distribution. This change occurs in the middle location of the chain instead of the chain end locations.     

Stepwise solid phase synthesis of uridylylated viral genome-linked peptides using uridylylated amino acid building blocks

The uridylylated amino acid building blocks 2-cyanoethyl-(N^α-9-fluorenylmethoxy-carbonyl-tyrosin-4-yl)-(2′,3′-di-O-acetyluridin-5′-yl) phosphate and 2-chlorophenyl-(N^α-fluorenyl-methoxycarbonyl-serin-3-yl)-(2′,3′-di-O-acetyluridin-5′-yl) phosphate have been used successfully in an on-line SPPS of the VPgpU from the polio, coxsackie and cowpea mosaic virus.     

Synthesis of an anion-binding amino acid

We achieved the synthesis of a derivative of phenylalanine with a diazamacrocycle on its side chain by macrocyclization of a dichloride on l-DOPA. We also report its incorporation into peptide structures by solid phase peptide synthesis which will lead to the development of artificial anion channels.     

Electrostatic solvation free energy of amino acid side chain analogs: implications for the validity of electrostatic linear response in water

Electrostatic free energies of solvation for 15 neutral amino acid side chain analogs are computed. We compare three methods of varying computational complexity and accuracy for three force fields: free energy simulations, Poisson-Boltzmann (PB), and linear response approximation (LRA) using AMBER, CHARMM, and OPLS-AA force fields. We find that deviations from simulation start at low charges for solutes. The approximate PB and LRA produce an overestimation of electrostatic solvation free energies for most of molecules studied here. These deviations are remarkably systematic. The variations among force fields are almost as large as the variations found among methods. Our study confirms that success of the approximate methods for electrostatic solvation free energies comes from their ability to evaluate free energy differences accurately.     

Diastereo- and enantioseparation of a N-Boc amino acid with a zwitterionic quinine-based stationary phase: Focus on the stereorecognition mechanism

A chiral chromatography method enabling the simultaneous diastereo- and enantioseparation of N^α-Boc-N⁴-(hydroorotyl)-4-aminophenylalanine [Boc-Aph(Hor)-OH, 1] was optimized with a quinine-based zwitterionic stationary phase. The polar-ionic eluent system consisting of ACN:MeOH:water—49.7:49.7:0.6 (v/v/v) with formic acid (4.0 mM) and diethylamine (2.5 mM), allowed the successful separation of the four acid stereoisomers: α_d,d-/d,l-1 = 1.08; α_d,l-/l,d-1 = 1.08; α_l,d-/l,l-1 = 1.40.     

Base-catalyzed hydrogenation: rationalizing the effects of catalyst and substrate structures and solvation

Ab initio molecular orbital calculations have been used to study the base-catalyzed hydrogenation of carbonyl compounds. It is found that these hydrogenation reactions share many common features with S(N)2 reactions. Both types of reactions are described by double-well energy profiles, with deep wells and a low or negative overall energy barrier in the gas phase, while the solution-phase profiles show very shallow wells and much higher barriers. For the hydrogenation reactions, the assembly of the highly ordered transition structure is found to be a major limiting factor to the rate of reaction. In the gas phase, the overall barriers for reactions catalyzed by Group I methoxides increase steadily down the group, due to the decreasing charge density on the metal. On the other hand, for Group II and Group III metals, the overall barriers decrease down the group, which is attributed to the increasing ionic character of the metal-oxygen bond. The reaction with B(OCH(3))(3) has an exceptionally high barrier, which is attributed to pi-electron donation from the oxygen lone pairs of the methoxy groups to the formally vacant p orbital on B, as well as to the high covalent character of the B-O bonds. In solution, these reactivity trends are generally the opposite of the corresponding gas-phase trends. While similar barriers are obtained for reactions catalyzed by methoxides and by tert-butoxides, reactions with benzyloxides have somewhat higher barriers. Aromatic ketones are found to be more reactive than purely aliphatic ketones. Moreover, comparison between catalytic hydrogenation of 2,2,5,5-tetramethylcyclopentanone and pivalophenone shows that factors such as steric effects may also be important in differentiating their reactivity. Solvation studies with a wide range of solvents indicate a steady decrease in barrier with decreasing solvent dielectric constant, with nonpolar solvents generally leading to considerably lower barriers than polar solvents. In practice, a good balance between polarity and catalyst solubility is required in selecting the most suitable solvent for the base-catalyzed hydrogenation reaction.     

Tunable N-substitution in zwitterionic benzoquinonemonoimine derivatives: metal coordination, tandemlike synthesis of zwitterionic metal complexes, and supramolecular structures

Full details on a very efficient transamination reaction for the synthesis of zwitterionic N,N-dialkyl-2-amino-5-alcoholate-1,4-benzoquinonemonoiminium derivatives [C6H2(=NHR)2(=O)2] 5-16 are reported. The molecular structures of zwitterions 5 (R=CH3) in 5.H2O, 13 (R=CH2CH2OMe), 15 (R=CH2CH2NMe2), and of the parent, unsubstituted system [C6H2(=NH2)2(=O)2] 4 in 4.H2O have been established by single-crystal X-ray diffraction. This one-pot preparation can be carried out in water, MeOH, or EtOH and allows access to new zwitterions with N-substituents bearing functionalities such as -OMe (13), -OH (9-12), NR1R2 with R1 = or not equal R2 (14-16) or an alkene (8), leading to a rich coordination chemistry and allowing fine-tuning of the supramolecular arrangements in the solid state. As previously described for 15, which reacted with Zn(acac)2 to afford the octahedral Zn(II) complex [Zn[C6H2(NCH2CH2NMe2)O(O)(NHCH2CH2NMe2)]2] (20), ligands 13 and 16 with coordinating "arms" afforded with Zn(acac)2 the 2:1 adducts [Zn[C6H2(NCH2CH2X)O(=O)(NHCH2CH2NX)]2] 19 (X=OMe) and 21 (X=NHEt), with N2O4 and N4O2 donor sets around the octahedral Zn(II) center, respectively. Furthermore, zwitterions 15 and 16 reacted with ZnCl2 to give the stable, crystallographically characterized Zn(II) zwitterionic complexes [ZnCl2[C6H2(NCH2CH2NR1R2)O(=O)(NHCH2CH2NHR1R2)]] 22 (R1=R2=Me) and 23 (R1=Et, R2=H) by means of an unprecedented, tandemlike synthesis in which 1) the two pendant amino groups of the organic benzoquinonemonoimine zwitterionic precursor favor metal coordination and proton transfer and 2) the saturated linker prevents pi-conjugation between the charges. The nature of the structural arrangements in the solid state for both inorganic (20, 22, 23) and organic (5, 9, 13, and 15) molecules is determined by subtle variations in the nature of the N-substituent on the zwitterion precursor.     

Supramolecular formation of large hydrogen-bonded rings in the structures of two amino acid derivatives

Two new amino acid derivatives N-(2-oxopyrrolidin-1-ylmethyl)-l-valine (PMV) and N,N-bis(2-oxopyrrolidin-1-ylmethyl)-β-alanine (PMA) were synthesized and their structures were determined by single crystal X-ray crystallography. The geometry and conformation of both molecular aggregates and their hydrogen bond networks are not similar. In the PMV crystal structure, PMV and the solvent water molecule are linked by O–H⋯O intermolecular hydrogen bonds resulting in two ring motifs R₁₂¹²(48) and R₄⁴(22). A three-dimensional supramolecular structure is formed by hydrogen bonds N–H⋯O between the layers. In the PMA crystal structure, each water molecule connects three PMA molecules through O–H⋯O intermolecular hydrogen bonds, and a ring motif R₄⁴(24) is formed in the structure. But there is no hydrogen bond interaction between the layers, in which van der Waals' interaction is involved only.     

Dielectric spectroscopy in the GHz region on fully hydrated zwitterionic amino acids

The complex dielectric permittivity of eight different amino acids in water solutions was determined in the frequency range from 0.2 to 20 GHz at room temperature, trying to span the whole range of solubility in each case. Two relaxations were observed at room temperature in this frequency range, which can be mainly assigned to the rotation of amino acids in the aqueous environment, and the reorientational motion of water molecules, respectively. Although the amino acids have a charged (zwitterionic) nature with huge dipole moments, the tendency towards dipolar alignment seems to be very weak, over the investigated concentration ranges. For these small bio-molecules, water screens solute-solute interactions and amino acids remain typically as isolated hydrated monomers. The dielectric results were used to estimate the number of water molecules restrained by each solute molecule. Finally, the comparison between the amino acid relaxation times made it possible to discuss the relationship between rotational dynamics and the structure and hydrodynamic coupling of the amino acid studied.     

Inference of the solvation energy parameters of amino acids using maximum entropy approach

We present a novel technique, based on the principle of maximum entropy, for deriving the solvation energy parameters of amino acids from the knowledge of the solvent accessible areas in experimentally determined native state structures as well as high quality decoys of proteins. We present the results of detailed studies and analyze the correlations of the solvation energy parameters with the standard hydrophobic scale. We study the ability of the inferred parameters to discriminate between the native state structures of proteins and their decoy conformations.