n --> pi* Interaction and n)(pi Pauli repulsion are antagonistic for protein stability.

In many common protein secondary structures, such as alpha-, 3(10), and polyproline II helices, an n --> pi* interaction places the adjacent backbone amide carbonyl groups in close proximity to each other. This interaction, which is reminiscent of the Burgi-Dunitz trajectory, involves delocalization of the lone pairs (n) of the oxygen (O(i-1)) of a peptide bond over the antibonding orbital (pi*) of C(i)=O(i) of the subsequent peptide bond. Such a proximal arrangement of the amide carbonyl groups should be opposed by the Pauli repulsion between the lone pairs (n) of O(i-1) and the bonding orbital (pi) of C(i)=O(i). We explored the conformational effects of this Pauli repulsion by employing common peptidomimetics, wherein the n --> pi* interaction is attenuated while the Pauli repulsion is retained. Our results indicate that this Pauli repulsion prevents the attainment of such proximal arrangement of the carbonyl groups in the absence of the n --> pi* interaction. This finding indicates that the poor mimicry of the amide bond by many peptidomimetics stems from their inability to partake in the n --> pi* interaction and emphasizes the quantum-mechanical nature of the interaction between adjacent amide carbonyl groups in proteins.