|dc.description.abstract||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.||en_US