Simulated annealing study of the pentacyclo-undecane cage amino acid tripeptides of the type [Ac-X-Y-Z-NHMe]

The conformational preferences of the four peptide analogues [A]=Ac-Ala-Ala-Ala-NHMe, [B]=Ac-Cage-Cage-Cage-NHMe, [C]=Ac-Ala-Cage-Ala-NHMe and [D]=Ac-Ala-Pro-Ala-NHMe were carried out using iterative simulated annealing (SA) at the molecular mechanics level using the amber force field. The overall conformational search indicates that the pentacyclo-undecane (PCU) Cage imposes a greater restriction on the conformational freedom of the tripeptide in comparison with proline. The first 20 low energy conformations were also analyzed for β-turns or reverse-turn characteristics. This theoretical study revealed that [D] proved to be the most effective β-turn promoter (35%) within the peptide series [A]-[D]. The pentacyclo-undecane amino acid exhibit promising β-turn characteristics in cases [B] and [C] (15%). In most cases for [A]-[D], the low energy structures are bent although none of the unique structures for [A] satisfy all three criteria for β-turns. The peptide sequences [B]-[D] can be classified as canonical reverse β-type I, II or III turns.