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Journal of Physical Organic Chemistry, 2009
The geometric parameters and relative stability of γ-and β-loop conformers of oligomers based on alanine were determined by the Kohn-Sham method (the B3LYP/6-31+G** approximation). The threedimensional architecture of the β-folded structure and protein α-helix was reproduced using Kohn-Sham calculations with periodic boundary conditions. The Bader quantum-topological molecular structure theory was used to reveal and quantitatively characterize noncovalent interatomic interactions in the secondary structures of model peptides under consideration. Earlier unnoticed additional noncovalent interactions stabilizing the structures under consideration were revealed. In β-loops, these are C-H … O and H … H interactions, and, in antiparallel β-folded structures, these are weak C β -H … H-C β interactions between side chains. Additional weak bonding interaction between C=O groups in position i and H-C β groups in position i + 3 was revealed for the protein α-helix; this interaction is usually ignored in amino acid folding simulations with the use of classic force fields.
Effect of intramolecular hydrogen-bond formation on the molecular conformation of amino acids
Communications Chemistry
The molecular conformation of the carboxyl group can be crucial for its chemical properties and intermolecular interactions, especially in complex molecular environments such as polypeptides. Here, we study the conformational behaviour of the model amino acid Nacetylproline in solution at room temperature with two-dimensional infrared spectroscopy. We find that the carboxyl group of N-acetylproline adopts two distinct conformations, synand anti-. In the syn-conformer the O-H group is oriented at~60 ∘ with respect to the C=O and in the anti-conformer the O-H is anti-parallel to the C=O. In hydrogen-bond accepting solvents such as dimethyl sulfoxide or water, we observe that, similar to simple carboxylic acids, around 20% of the-COOH groups adopt an anti-conformation. However, when Nacetylproline is dissolved in a weakly hydrogen-bond accepting solvent (acetonitrile), we observe the formation of a strong intramolecular hydrogen bond between the carboxyl group in the anti-conformation and the amide group, which stabilizes the anti-conformer, increasing its relative abundance to~60%.
QTAIM Study of an α-Helix Hydrogen Bond Network
Journal of Physical Chemistry B, 2009
The structures of 19 R-helical alanine-based peptides, 13 amino acids in length, have been fully optimized using density functional theory and analyzed by means of the quantum theory of atoms in molecules. Two types of N-H · · · O bonds and one type of C-H · · · O bond have been identified. The value of the electron density at hydrogen bond critical points corresponding to N-H · · · O interactions is higher than that of C-H · · · O interactions. The effect of amino acid substitution at the central position of the peptide on the hydrogen bond network of the R-helix has been assessed. The strength of the hydrogen bond network, measured as the summation of the electron density over the hydrogen bond critical points, may be used to explain experimental relative helix propensities of amino acids in cases where solvation and entropic effects cannot.
Modeling the interplay of inter- and intramolecular hydrogen bonding in conformational polymorphs
Chemical Physics, 2008
The predicted stability differences of the conformational polymorphs of oxalyl dihydrazide and ortho-acetamidobenzamide are unrealistically large when the modeling of intermolecular energies is solely based on the isolated-molecule charge density, neglecting charge density polarization. Ab initio calculated crystal electron densities showed qualitative differences depending on the spatial arrangement of molecules in the lattice with the greatest variations observed for polymorphs that differ in the extent of inter-and intramolecular hydrogen bonding. We show that accounting for induction dramatically alters the calculated stability order of the polymorphs and reduces their predicted stability differences to be in better agreement with experiment. Given the challenges in modeling conformational polymorphs with marked differences in hydrogen bonding geometries, we performed an extensive periodic density functional study with a range of exchange-correlation functionals using both atomic and plane wave basis sets. Although such electronic structure methods model the electrostatic and polarization contributions well, the underestimation of dispersion interactions by current exchange-correlation functionals limits their applicability. The use of an empirical dispersion-corrected density functional method consistently reduces the structural deviations between the experimental and energy minimized crystal structures and achieves plausible stability differences. Thus, we have established which types of models may give worthwhile relative energies for crystal structures and other condensed phases of flexible molecules with intra-and intermolecular hydrogen bonding capabilities, advancing the possibility of simulation studies on polymorphic pharmaceuticals.
Ab initio conformational analysis of N-formyl l-alanine amide including electron correlation
Journal of Molecular Structure, 2001
The conformational properties of N-formyl l-alanine amide (ALA) were investigated using RMP2/6-311G pp ab initio gradient geometry optimization. One hundred forty four structures of ALA were optimized at 308 grid points in its f(N± C(a)), c(C(a)±C 0 ) conformational space. Using cubic spline functions, the grid structures were then used to construct analytical representations of complete surfaces, in f ,c -space, of bond lengths, bond angles, torsional sensitivity and electrostatic atomic charges. Analyses show that, in agreement with previous studies, the right-handed helical conformation, a R , is not a local energy minimum of the potential energy surface of ALA. Comparisons with protein crystallographic data show that the characteristic differences between geometrical trends in dipeptides and proteins, previously found for ab initio dipeptide structures obtained without electron correlation, are also found in the electron-correlated geometries. In contrast to generally accepted features of force ®elds used in empirical molecular modeling, partial atomic charges obtained by the CHELPG method are found to be not constant, but to vary signi®cantly throughout the f,c-space. By comparing RHF and MP2 structures, the effects of dispersion forces on ALA were studied, revealing molecular contractions for those conformations, in which small adjustments of torsional angles entail large changes in non-bonded distances. q
QTAIM study of an alpha-helix hydrogen bond network
2009
The structures of 19 R-helical alanine-based peptides, 13 amino acids in length, have been fully optimized using density functional theory and analyzed by means of the quantum theory of atoms in molecules. Two types of N-H · · · O bonds and one type of C-H · · · O bond have been identified. The value of the electron density at hydrogen bond critical points corresponding to N-H · · · O interactions is higher than that of C-H · · · O interactions. The effect of amino acid substitution at the central position of the peptide on the hydrogen bond network of the R-helix has been assessed. The strength of the hydrogen bond network, measured as the summation of the electron density over the hydrogen bond critical points, may be used to explain experimental relative helix propensities of amino acids in cases where solvation and entropic effects cannot.
Journal of Molecular Structure, 2010
The backbone-side-chain interactions in the peptide secondary structures are studied by the density functional theory methods with/without periodic boundary conditions. The alanine-based two-stranded b-sheet structure infinite models and the cluster models of the C5 structures modified by the glutamic acid residue are considered. Several low-energy structures have been localized in the BLYP/plane-wave and the BLYP/6-311++G** approximations. Combined use of the quantum-topological analysis of the electron density and frequency shifts enables us to detect and describe quantitatively the non-covalent interactions and H-bonds. We found that the strongest backbone-side-chain interaction ($37 kJ/mol) is due to the intra-chain H-bond formed by the C@O backbone group and by the COOH side-chain group. The OH. . .O distance equals to 1.727 Å and the frequency shift of the OH stretching vibration is 370 cm À1 . The polar side-chains interaction is studied in the infinite model of the alanine-based two-stranded b-sheet structure modified by the glutamic acid/lysine residues. Moderate inter-chain H-bond ($40 kJ/ mol) is formed by glutamic acid COOH group and lysine NH 2 group. The OH. . .N distance equals to 1.707 Å and the frequency shift of the OH stretching vibration is 770 cm À1 .
Journal of Molecular Structure: THEOCHEM, 2005
All the plausible conformations of b-aminoacrolein (AMAC) have been investigated by the Bekes-Lee-Yang-Parr (B3LYP) nonlocal density functional with extended 6-311CCG** basis set for studying the stability order of conformers and the various possibilities of intramolecular hydrogen bonding formation. In general the ketoamine (KA) conformers of AMAC, by mean average, are more stable than the corresponding enolimine (EI) and ketoimine (KI) analogues and this stability is mainly due to the p-electron resonance in these conformers that established by NH2 functional group. The contribution of resonance to the stability of chelated KA conformers is about 75.6 kJ/mol, which is greater than that of the hydrogen bond energy (E HB Z35.0 kJ/mol). The relative decreasing order of the various hydrogen bond energies was found to be: O-H/N imine (strong)ON amine-H/O keto (normal)ON imine-H/O hydroxyl (weak) O N imine-H/O keto (weak). Hydrogen bond energies for all systems were obtained from the method that we called related rotamers method (RRM). The topological properties of the electron density contributions for various type of intramolecular hydrogen bond have been analyzed in term of the Bader theory of atoms in molecules (AIM). The results of these calculations support the previous calculations, which obtained by the related rotamer methods.