Complete Computational Reaction Mechanism for Foldamer-Catalyzed Aldol Condensation

Foldamers, small synthetic peptides made of α and β-amino acids, have been found to be efficient catalysts for carbon-carbon bond-forming aldol reactions; of particular interest is their ability to catalyze macrocycle ring closure reactions. These catalysts feature a pair of amine groups that are aligned by the helical conformation and act in concert. Kinetic measurements show that the rate of the reaction depends on the identity of the amine side chains present. However, such kinetic analyses and other characterization techniques (e.g. mass spectrometry) can provide only limited information regarding the overall mechanism and rate-determining step of foldamer catalysis. We use semi-empirical density functional tight binding quantum mechanics molecular mechanics metadynamics simulations to determine the free energy and barrier for all elementary steps involved in the ring closure aldol reactions. We have performed calculations for 44 elementary reaction steps to identify key trends regarding amine identity, and provide insight into the intermediates and rate-limiting step of the catalytic cycle. From our results and other known aldol catalysts, we propose foldamer mutants which simulations predict to be better catalysts.