Sequence-dependent pKa shift induced by molecular self-assembly: insights from computer simulation.

Area of Science:

• Biophysical Chemistry
• Catalysis
• Molecular Self-Assembly

Background:

• Controlling catalytic activity via molecular self-assembly is crucial.
• Two beta-peptide isomers exhibit differing amine catalyst activity in retro-aldol reactions, linked to aggregation.
• The globally amphiphilic (GA) isomer shows higher activity, attributed to aggregate formation.

Purpose of the Study:

• Investigate the self-assembly and catalytic activity of two beta-peptide isomers.
• Utilize constant pH molecular dynamics (CPHMD) for an atomistic model.
• Understand the relationship between aggregation, pKa shifts, and catalytic performance.

Main Methods:

• Atomistic molecular dynamics (MD) simulations.
• Constant pH molecular dynamics (CPHMD) in implicit solvent.
• Analysis of aggregate formation and pKa shifts in beta-peptides.

Main Results:

• Globally amphiphilic (GA) beta-peptide isomer forms large aggregates, while the non-GA isomer forms small aggregates (3-4 molecules).
• Significantly higher pKa shift observed for beta-lysine (βK) residues in the GA isomer's large aggregates.
• Buried βK residues are fully deprotonated; pKa shifts in others correlate with solvent-exposed βK residue clustering.

Conclusions:

• Simulation results align with experimental findings on beta-peptide catalytic activity.
• Self-assembly into large aggregates enhances amine catalysis by increasing beta-lysine (βK) residue deprotonation.
• Molecular dynamics simulations are effective tools for elucidating structure-activity relationships in self-assembling catalysts.