DFT study on reaction mechanisms of cyclic dipeptide generation

In this work, three possible reaction pathways (Path 1, Path 2 and Path 3) for the generation process of cyclic dipeptide from amino acid have been investigated in detail using density functional theory. Path 1 and Path 2 are the intramolecular reaction processes, while Path 3 involves the intermolecular reaction process that assisted with water molecule. Our calculated results indicate that Path 3 is more energy favorable than Path 1 and Path 2. There are four steps in Path 3 proceed from the amino acid to cyclic dipeptide. The first step is two adjacent amino acids to form precursor of dipeptide, the second step is the removal of water molecule of precursor of dipeptide for the formation of the linear dipeptide, the third step is generation of precursor of cyclic dipeptide associated with other hydrogen atom transfer, and the last step is another dehydration process to generate the final product of cyclic dipeptide. Moreover, the obtained results indicate that the generation mechanisms of different cyclic dipeptides are similar, and the energy barrier of the rate-determined step influenced somewhat by the hydrophilic or hydrophobic group linked to the C_α atom. Additionally, the potential energy profiles suggest that the generation reactions of the studied nine cyclic dipeptides are exothermic processes. The detailed mechanisms should be helpful for people to understanding the title reaction at the molecular level, and the proposed novel intermolecular process might provide valuable insights on rational improve reaction condition for this type of reaction.