Theoretical Characterization of The Protonation Sites of Mycolactones A/B and C by The Oniom Method

Mycolactones are infectious factors of Mycobacterium ulcerans, the causative agent of Buruli ulcer. This work focuses on mycolactones A/B and C, the most virulent forms found in Africa and Australia. Each of these molecules is formed from a lactone ring and two side chains. The study focuses on the protonation reactions on each of the heteroatoms of the two mycolactones, in order to determine their preferential site. By implementing the ONIOM method, at the level (B3LYP/6-311+G (d,p): AM1) we determined, for each of the molecules and for each of the heteroatoms, the proton affinity (PA) and the gas phase basicity (GB). The choice of the Density Functional (DFT/B3LYP) allowed us to obtain very encouraging results. As for the choice of split-valence and triple-dzeta bases, they are sufficiently extended and the consideration of diffuse and polarization functions is important when it comes to intermolecular interactions. In total, the computational results identified the O5sp2 heteroatom as the likely site of gas-phase protonation of the two mycolactones. The identification of this site constitutes a significant advance in the implementation of a methodology for the annihilation of the infection and destruction effects of these two toxins.