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 β-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 β-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 βK-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 βK residues become entirely deprotonated, and the pK(a) shift for other titratable βK residues is accompanied mainly by a clustering of solvent exposed βK residues. We conclude that simulations can be used to understand catalytic activity due to self-assembly.