We expanded our previous mapping of peptide condensation reaction mechanism from the linear dipeptide formation to the cyclization reaction that results in diketopiperazines. The overarching theme of our gas phase and water solvated model investigations is a reaction network that connects all intermediates via proton-transfer pathways. We conducted the simulations to be predictive in a range of environments, such as gas phase, hydrothermal aqueous, deliquescent salt, and bulk water. While the free energy profiles are similar to the linear peptide; the presence of the cis amide bond leading to a pre-arranged vicinity of the two reacting groups, and the role of explicit solvent molecules revealed new mechanistic insights that differentiate the linear versus cyclic peptide formation/hydrolysis reactions. The rate determining step corresponds to the final water elimination reaction using the most realistic computational models with both implicit and explicit water solvation models at neutral pH. At high pH, the highest barrier corresponds to the C–N bond formation at lowered free energy, while at low pH the water elimination step’s barrier increases by close to 30% and effectively shutting down the reaction. Due to the central role of proton-transfer, we studied the impact of nuclear wave functions on all active H-centers. Utilizing two quantum protons, we document up to 0.1 Å impact on H positions, ca. 20 kJ mol-1 tunneling effects, and a significant change to the shape of the potential energy surface in comparison to the classical DFT calculation. The calculated reaction rates well reproduce the experimentally determined values at hydrothermal conditions.

This article is Open Access

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