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    N/pi and N/sigma interactions of the amide linkage with its N-substituents : a quantum chemical study
    (2002) Demir, Özlem
    The overall contribution of backbone-backbone H-bonding to the stability of proteins remains an unresolved issue. However, a wealth of spectroscopic, structural, and thermodynamic evidence indicates that the strength of those interactions increases on going from turn or 310-helix to α-helix to β-sheet. This implies that the electronic properties of the amino acid side chains and their local interactions with the peptide bonds might play a role in secondary structure stability. One such interaction is suggested by the apparent dependence of thermodynamic β-sheet propensities, and of 15N NMR chemical shifts of oligopeptides, on resonance constants of the side chains: electron-density shift from the i+1 residue into the i, i+1 peptide bond which would increase basicity of the carbonyl O and thereby strengthen its H-bond. To test this counterintuitive proposition, N/π and N/σ interactions of the amide linkage with its N substituents were investigated. Effects of substitution have been characterized by computational examination of the changes in energy, molecular geometry, electron density distribution, and electronic structure, in three series of compounds: (1) formamides HC(=X)NY2 (X=O, S, Se; Y=H, CH3, F, Cl, Br); (2) 2,3,-endo,endo-disubstituted N-acyl-7-azabicyclo(2.2.1)heptanes and 2,3,-endo,endo-disubstituted 7-bicyclo(2.2.1)-heptyl cations; and (3) 3-substituted 5,6-diaza-1- bicyclo(2.1.1)hexyl cations. Both ab initio (MP2) and DFT methods were employed using Pople’s basis sets (6-31+G(2d), 6-31+G*, and 6-31G*). N-halo substitution effect on the potential energy surface of simple formamide derivatives is found to be largely related to the electronegativity of the substituents. The exception to this general trend is found in the case of the F effect on the transition structures for inversion, where F lp donation appears to assist π-bonding across the C-N bond, stabilizing the charge polarized resonance form of the amide group. This is supported by the examination of the variation in bond v distances, bond orders, energy and extension of the canonical π-symmetry orbitals, and NBO occupancies of the localized orbitals. On the other hand, the implied π-bonding across the N-F bond is not reflected in the group transfer energies obtained as heats of the isodesmic substitution reaction, the effect being apparently too small in comparison to the total bond energies. In accord with the experimental data, N-acetyl-7-azabicyclo(2.2.1)heptane is found to be highly pyramidalized on N7. However, due to the very small barrier to inversion, chalcogen substitution, as in N-thioacetyl and N-selenoacetyl- derivatives, results in virtual planarity of the amide N. The planar geometry is readily distorted by remote substitution in 2,3-endo,endodisubstituted N-thioacetyl-7-azabicyclo(2.2.1)-heptanes. The direction of pyramidalization is the same for strongly electron-donating substituents and strongly electron-withdrawing substituents. The dual parameter treatment suggests that in the first case pyramidalization depends largely on the NBO energies of the occupied orbitals of the bicycloheptane C-C bonds, while in the second case both the occupied and vacant orbitals interact with the N center. Examination of the electron density shifts associated with the change in conformation of the π-donor substituents confirms that the thioamide N acts as a resonance acceptor of the σ C-C density. Finally, 5,6-diaza-1-bicyclo(2.1.1)hexyl cation is found to be an excellent model system to probe π-donor capacity of the range of substituents, including all the coded amni acid side chains, even in their ionized forms. The first scale of substituent constants is obtained to characterize resonance interactions in the σ-bond systems, related to the scale of conventional experimental σR constants. The findings of the present study suggest that the amide linkage can indeed act as a resonance acceptor of π- and σ-density of its N substituents. These results may further our understanding of the local interactions in proteins and the origin of secondary structure propensities of the coded amino acids.