Sequence-Dependent pKa Shift Induced by Molecular Self-Assembly: Insights from Computer Simulation

The control of catalytic activity using molecular self-assembly is of fundamental interest. Recent experiments (Muller et al., Angew. Chem., Int. Ed., 2009, 48, 922-925) have demonstrated that two sequence isomers of beta-peptides show. remarkably different activity as an amine catalyst for a retro-aldol cleavage reaction, a difference attributed to the ability of one of the sequences to form large aggregates. The self-assembly and catalytic activity of these two isomers are investigated using constant pH molecular dynamics (CPHMD), for an atomistic model of fl-peptides in implicit solvent. Simulations show that the globally amphiphilic (GA) isomer, which experimentally has high activity, forms large aggregates, while the non-GA isomer forms aggregates that are at most three or four molecules in size. The pK(a) shift of the beta K-residues is significantly higher in the GA isomers that make a large aggregate. Since the decrease in pK(a) of the side-chain ammonium group is the main driving force for amine catalysis, the calculations are consistent with experiment. We find that the buried beta K residues become entirely deprotonated, and the pK(a) shift for other titratable beta K residues is accompanied mainly by a clustering of solvent exposed beta K residues. We conclude that simulations can be used to understand catalytic activity due to self-assembly.