Switching conformation of cyclo(histidyl-histidyl) dipeptide: dynamics and density functional theory study

Abstract

The backbone–side-chain interaction and switching propensity of cyclo(histidyl-histidyl) dipeptide from a folded–folded to unfolded–unfolded state and vice versa have been studied, combining molecular dynamics and density functional theory. Dynamic simulation for a time scale of 3 ns confirms the switching behaviour of the dipeptide, with a folded–folded structure having the maximum probability of occurrence. The geometry optimisation of the folded–folded (U-shaped) and unfolded–unfolded (linear-shaped) structure in the gas phase predicts the latter to be more stable. The ring-puckering study indicates a boat conformation for the six-membered diketopiperazine (DKP) ring. All the above studies are found to correlate well with the earlier experimental results. The interaction of the water molecules in the first solvation shell of cyclo(histidyl-histidyl) dipeptide lowers the energy barrier more for the folded–folded (U-shaped) structure than for its counterpart. Water molecules are found to act as a bridge between the side-chain imidazole and the DKP ring, thus deciding the conformation of the dipeptide. The structural propensities are found to be in good agreement with the obtained electronic effects. This study would be helpful in understanding the conformational preferences of cyclic dipeptides in the aqueous medium.