Proton transfer at the carboxylic sites of amino acids: A single water molecule catalyzed process

Ab initio calculations at MP2 level of theory were used to study the proton transfer at the carboxylic sites of amino acids, in the isolated, mono‐ and di‐hydrated forms. In the case of water dimer, two interaction modes with glycine neutral structures (see Fig. 3 ) were explored, corresponding to the concerted and stepwise reaction pathways. Their transition states can be described as (H₂O? H? OH₂)⁺ [Fig. 4 (a)] and (H₂O‐‐‐H? OH₂)⁺ [Fig. 4 (b)], respectively. The energy analysis indicated that the concerted pathway is preferred. In the isolated, mono‐ and di‐hydrated glycine complexes, the activation barriers of the proton transfer at the carboxylic sites were calculated to be 34.49, 16.59, and 13.36 kcal mol^?1, respectively. It was thus shown that the proton transfer is significantly assisted and catalyzed by water monomer so that it can take place at room temperature. Instead, the further addition of water molecules plays solvent effects rather than catalytic effects to this proton transfer process. The above results obtained with discrete water molecules were supported by the solvent continuum calculated data. It was also observed that the heavy dependence of the solvent continuum models on dipole moments may produce misleading results. © 2008 Wiley Periodicals, Inc. Int J Quantum Chem, 2009     

Synthesis and structural characterization of homochiral homo-oligomers of parent cis- and trans-furanoid-β-amino acids

The synthesis of homochiral homo-oligomers of cis- and trans-3-aminotetrahydrofuran-2-carboxylic acids (parent cis- and trans-furanoid-β-amino acids, referred to as "cis-/trans-FAA") has been carried out to understand their secondary structures and their dependence on the ring heteroatom. The oligomers of two diastereomers have been shown to have a distinct left-handed helicity. The cis-FAA homo-oligomers show a 14-helix structure, in contrast to the homo-oligomers of cis-ACPC, which adopt a sheet like structure. The trans-FAA homo-oligomers were found to adopt a 12-helix structure, the same trend found in trans-ACPC homo-oligomers. With the help of ab initio calculations, the structural features of cis-ACPC and cis-FAA hexamers were compared. We believe that the more compact packing of the cis-FAA hexapeptide should be due to a more favorable interaction between the ring and the backbone amide hydrogen.     

Uncatalyzed peptide bond formation between two double amino acid molecules in the gas phase

The gas phase mechanism for peptide bond formation between two double amino acid (DAA) molecules ((NH₂)₂C(COOH)₂) is investigated in the absence of any catalysts. Two different paths, concerted and stepwise, each leading to both cis and trans DAA‐DAA dipeptide products (four mechanisms total) are examined on the basis of theoretical calculations carried out at the CCSD(T)/aug‐cc‐pVDZ//MP2/aug‐cc‐pVDZ level. The investigation indicates that the concerted mechanism leading to the trans configuration of the peptide bond in the DAA‐DAA dipeptide product is thermodynamically favored by about 5 kcal mol^?1 and requires slightly less energy than the remaining pathways considered. Moreover, the peptide bond formation process between two DAA molecules in the gas phase resembles the analogous reactions between two natural amino acids.     

Interaction Modes and Absolute Affinities of α‐Amino Acids for Mn2+: A Comprehensive Picture

Manganese is involved as a cofactor in the activation of numerous enzymes as well as the oxygen‐evolving complex of photosystem II. Full understanding of the role played by the Mn²⁺ ion requires detailed knowledge of the interaction modes and energies of manganese with its various environments, a knowledge that is far from complete. To bring detailed insight into the local interactions of Mn in metallopeptides and proteins, theoretical studies employing first‐principles quantum mechanical calculations are carried out on [Mn‐amino acid]²⁺ complexes involving all 20 natural α‐amino acids (AAs). Detailed investigation of [Mn‐serine]²⁺_, [Mn‐cysteine]²⁺, [Mn‐phenylalanine]²⁺, [Mn‐tyrosine]²⁺, and [Mn‐tryptophan]²⁺ indicates that with an electron‐rich side chain, the most stable species involves interaction of Mn²⁺ with carbonyl oxygen, amino nitrogen, and an electron‐rich section of the side chain of the AA in its canonical form. This is in sharp contrast with aliphatic side chains for which a salt bridge is formed. For aromatic AAs, complexation to manganese leads to partial oxidation as well as aromaticity reduction. Despite multisite binding, AAs do not generate strong enough ligand fields to switch the metal to a low‐ or even intermediate‐spin ground state. The affinities of Mn²⁺ for all AAs are reported at the B3LYP and CCSD(T) levels of theory, thereby providing the first complete series of affinities for a divalent metal ion. The trends are compared with those of other cations for which affinities of all AAs have been previously obtained.     

Glycine Dimers: Structure,Stability, and Medium Effects

We report a study on different ionization states and conformations of the bimolecular (Gly)₂ system by means of quantum mechanical calculations. Optimized geometries for energy minima of the glycine dimer, as well as relative energies and free energies were computed as a function of the medium: gas phase, nonpolar polarizable solvent, and aqueous solution. The polarizable continuum model was employed to account for solvation effects. Energy calculations were done using the MP2/aug‐cc‐pVTZ and B3LYP/6‐311+G(2df,2p) methods on B3LYP/6‐31+G(d,p) optimized structures (some single‐point energy calculations were also done using the B3PW91 and PBE1KCIS methods). Ionized forms of the glycine dimer (either zwitterion–zwitterion or neutral–zwitterion) are predicted to exist in all media, in contrast to amino acid monomers. In aqueous solution, dimerization is an exergonic process (?4 kcal mol^?1). Thus, according to our results, zwitterion–zwitterion Gly dimers might be abundant in supersaturated glycine aqueous solutions, a fact that has been connected with the structure of α‐glycine crystals but that remains controversial in the literature. Another noticeable result is that zwitterion–zwitterion interactions are substantially underestimated when computed using methods based on density functional theory. For comparison, some calculations for the dimer of the simplest chiral amino acid alanine were done as well and differences to the glycine dimer are discussed.     

Synthesis and Structure of α/δ‐Hybrid Peptides—Access to Novel Helix Patterns in Foldamers

Origami peptides : A novel class of foldamers consisting of α/δ‐hybrid peptides has been investigated theoretically and experimentally by exploiting the rigidity of the side chain of a new δ‐amino acid prepared from D ‐glucose and D ‐xylose with a furanose side chain (see figure).

     

Theoretical evidence for pyramidalized bicyclic serine enolates in highly diastereoselective alkylations

A new chiral serine equivalent and its enantiomer have been synthesized from (S)- and (R)-N-Boc-serine methyl esters (Boc: tert-butyloxycarbonyl). The use of these compounds as chiral building blocks has been demonstrated in the synthesis of alpha-alkyl alpha-amino acids by diastereoselective potassium enolate alkylation reactions and subsequent acid hydrolyses. Theoretical studies were performed to elucidate the stereochemical outcome of both the formation of five-membered cyclic N,O-acetals and the subsequent alkylation process, which occurs with total retention of configuration. This feature could be explained in terms of the high degree of pyramidalization of enolate intermediates.     

Interaction of carboranes with biomolecules: formation of dihydrogen bonds.

Noncovalent interactions of the polyhedral carborane 1-carba-closo-dodecaborane (CB(11)H(12))(-) with building blocks of biomolecules, modelled by glycine (GLY), serine (SER), phenylalanine (PHE), glutamic acid (GLU), lysine (LYS) and arginine (ARG), were investigated in vacuo by molecular dynamics simulations with the UFF empirical potential. Selected structures were further studied by accurate ab initio quantum chemical procedures. Interactions with a peptide bond (GLY-SER dipeptide) and a nucleic acid building block (guanine) were also considered. The RESP and NPA charges of carboranes and small model systems are compared and their use is discussed. The dominant interaction between carboranes and biomolecules is the formation of unconventional proton-hydride hydrogen bonds (dihydrogen bonds) characterized by a short distance between hydrogen atoms (as close as 1.8 A) and an average strength in the range of 4.2-5.8 kcal mol(-1). The total stabilization energy of complexes investigated is rather large, and the largest value (approximately 15 kcal mol(-1)) was found for the carborane complexes with ARG and the GLY-SER dipeptide. These interactions are ubiquitous under geometrical constraints influencing the strength of the interaction. The carborane forms dihydrogen bonds with biomolecules preferably with the hydrogen atoms of its lower hemisphere (i.e. the part of the cage opposite to the carbon atom). These two geometrical factors can be used to explain the specificity of inhibition of HIV protease by carboranes.     

DNA base trimers: empirical and quantum chemical ab initio calculations versus experiment in vacuo

A complete scan of the potential‐energy surfaces for selected DNA base trimers has been performed by a molecular dynamics/quenching technique using the force field of Cornell et al. implemented in the AMBER7 program. The resulting most stable/populated structures were then reoptimized at a correlated ab initio level by employing resolution of the identity, Møller–Plesset second‐order perturbation theory (RI‐MP2). A systematic study of these trimers at such a complete level of electronic structure theory is presented for the first time. We show that prior experimental and theoretical interpretations were incorrect in assuming that the most stable structures of the methylated trimers corresponded to planar systems characterized by cyclic intermolecular hydrogen bonding. We found that stacked structures of two bases with the third base in a T‐shape arrangement are the global minima in all of the methylated systems: they are more stable than the cyclic planar structures by about 10 kcal mol^?1. The different behaviors of nonmethylated and methylated trimers is also discussed. The high‐level geometries and interaction energies computed for the trimers serve also as a reference for the testing of recently developed density functional theory (DFT) functionals with respect to their ability to correctly describe the balance between the electrostatic and dispersion contributions that bind these trimers together. The recently reported M052X functional with a polarized triple‐zeta basis set predicts 11 uracil trimer interaction energies with a root‐mean‐square error of 2.3 kcal mol^?1 relative to highly correlated ab initio theoretical calculations.     

Conformers of gaseous proline

Accurate geometries, relative energies, rotational and quartic centrifugal distortion constants, dipole moments, harmonic vibrational frequencies, and infrared intensities were determined from ab initio electronic structure calculations for eighteen conformers of the neutral form of the amino acid L-proline. Only four conformers have notable population at low and moderate temperature. The second most stable conformer is only 2+/-2 kJ mol(-1) above the global minimum, while the third and fourth conformers are nearly degenerate and have an excess energy of 7+/-2 kJ mol(-1) relative to the global minimum. All four conformers have one hydrogen bond: N.HO in the lower energy pair of conformers, and NH.O in the higher energy pair of conformers. The conformer pairs differ only in their ring puckering. The relative energies of the conformers include corrections for valence electron correlation, extrapolated to the complete basis set limit, as well as core correlation and relativistic effects. Structural features of the pyrrolidine ring of proline are discussed by using the concept of pseudorotation. The accurate rotational and quartic centrifugal distortion constants as well as the vibrational frequencies and infrared intensities should aid identification and characterization of the conformers of L-proline by rotational and vibrational spectroscopy, respectively. Bonding features of L-proline, especially intramolecular hydrogen bonds, were investigated by the atoms-in-molecules (AIM) technique.     

The Shape of the Simplest Non-proteinogenic Amino Acid α-Aminoisobutyric Acid (Aib)

The simplest non-proteinogenic amino acid α-aminoisobutyric acid (Aib), an analogue of glycine and alanine, has been vaporized by laser ablation and probed by high-resolution Fourier transform microwave spectroscopic techniques. Comparison of the experimental rotational and ¹⁴N nuclear quadrupole constants with that predicted ab initio has allowed the identification of three conformers of Aib exhibiting three types of hydrogen-bond interactions I (NH⋅⋅⋅O=C, cis-COOH), II (OH⋅⋅⋅N, trans-COOH), and III (N−H⋅⋅⋅O−H, cis-COOH) within the amino acid backbone. The observation of conformer III, not detected previously for related proteinogenic amino acids with a nonpolar side chain in a supersonic expansion, indicates that the presence of the methyl groups should restrict the conformational relaxation from conformer Aib-III to Aib-I. For conformer Aib-II, the rotational spectra of the ¹³C isotopomers reveal a tunneling motion arising from the two equivalent methyl groups in the molecule. The observation of a single spectrum at the midpoint between those predicted for the two ¹³C of the methyl groups has been explained by considering a double-minimum potential function with a low-energy interconversion barrier for a large amplitude internal motion. This singular fact has been corroborated by the anomalous centrifugal distortion effects determined in conformer Aib-II.     

Conformations of Serine in Aqueous Solutions as Revealed by Vibrational Circular Dichroism

Vibrational circular dichroism (VCD) spectroscopy is utilized to reveal the detailed conformational distributions of the dominant serine species in aqueous solutions under three representative pH conditions of 1.0, 5.7, and 13.0, together with vibrational absorption (VA) spectroscopy, density functional theory (DFT), and molecular dynamics simulation. The experimental VA and VCD spectra of serine in H₂O and D₂O in the fingerprint region under three pH values are obtained. DFT calculations at the B3LYP/6‐311++G(d,p) level are carried out for the protonated, zwitterionic, and deprotonated serine species. The lowest‐energy conformers of all three species are identified and their corresponding VA and VCD spectra simulated. A comparison between the gas‐phase simulations and the experimental VA and VCD spectra suggests that one or two of the most stable conformers of each species contribute predominantly to the observed data, although some discrepancies are noted. To account for the solvent effects, both the polarizable continuum model and the explicit solvation model are considered. Hydrogen‐bonded protonated, zwitterionic, and deprotonated serine–(water)₆ clusters are constructed based on radial distribution function analyses and molecular dynamics snapshots. Geometry optimization and VA and VCD simulations are performed for these clusters at the B3LYP/6‐311++G(d,p) level. Inclusion of the explicit water molecules is found to improve the agreement between theory and experiment noticeably in all three cases, thus enabling conclusive conformational distribution analyses of serine in aqueous solutions directly.     

Conformers of gaseous protonated glycine

Ab initio geometry optimizations were performed on gaseous protonated glycine using the second-order Møller–Plesset perturbation theory with the 6-31G*, 6-31G**, 6-31+G**, and 6-311+G** basis sets. Eight energy minima and 12 saddle points in the low-energy region of the electronic potential energy surface were characterized. The global minimum was an amino N-protonated conformer containing an ionic H bond between the (SINGLE BOND)NH₃⁺ and O(DOUBLE BOND)C(DIAGONAL BOND)(DIAGONAL BOND) groups. The lowest energy O-protonated conformer was stabilized by a conjugative attraction between the nitrogen lone-pair electrons and the positively charged planar fragment (SINGLE BOND)C(OH)₂⁺. Relative electronic energies of the nine N- and 11 O-protonated species fall in the ranges of 0–10 and 30–40 kcal mol⁻¹. At room temperature the equilibrium distribution contained the most stable N-protonated conformer almost exclusively. Additional subjects for investigation include the effects of basis set and electron correlation on the predicted structures, nonbonded interactions that influence the relative stability of protonated conformers, conformational interconversions based on intrinsic reaction coordinate calculations, and kinetic pathways for protonation and associated changes in Gibbs free energy. The work provides geometric, energetic, and thermodynamic data pertinent to the study of gas-phase ion chemistry of amino acids and peptides. © 1998 John Wiley & Sons, Inc. J Comput Chem 19: 1862–1876, 1998     

Ab Initio Theoretical Investigation on the Geometrical and Electronic Structures of AlAun-/0 (n = 2-4) Clusters

A systematic density functional theory and wave function theory investigation on the geometrical and electronic properties of AlAu n 0/-(n=2-4) clusters has been performed in this work. AlAu n-anions prove to possess ground states of the V-shaped C2v AlAu2 - , umbrella-shaped C3v AlAu3- , and perfect tetrahedral T d AlAu4- , while their neutrals favor the V-shaped C2v AlAu2 , perfect planar triangular D3h AlAu3 , and severely distorted C s AlAu4 , respectively. Aluminum aurides appear to be analogous to the corresponding aluminum hydrides, expect C s AlAu4 . Molecular orbitals (MOs) analyses also support this conclusion. Detailed orbital analyses indicate that Au 6s makes 94-96% and Au 5d makes 6-4% contribution to the Au-based orbitals in Al-Au bonds, which is smaller than the BAu n0/- series, partially reflecting the relativistic effect of gold. The one-electron detachment energies of the anions and characteristic stretching vibrational frequencies of Al-Au bonds between 100-400 cm -1 have been calculated to facilitate future experimental characterization of these clusters.