The retro-aldolase mechanism of methodol catalysed by the catalytic antibody 33F12 is described based on the exploration of the free energy landscape obtained with QM/MM methods. The amino acids involved in the reaction have been identified, as well as their specific role played in the active site and in the flexibility of the loops. Finally, the comparison with a de novo enzyme RA95.5-8F provides a deeper understanding of catalytic differences between such different protein scaffolds.