Free energy landscapes for amyloidogenic tetrapeptides dimerization

Area of Science:

• Biophysics
• Computational Chemistry
• Materials Science

Background:

• Peptide oligomerization is crucial for understanding fibril formation, relevant to diseases like Alzheimer's.
• Previous studies identified specific residues (phenylalanine, valine) associated with fibril formation in short peptides.
• The early stages of oligomerization are key determinants of overall fibrillogenic propensity.

Purpose of the Study:

• To investigate the thermodynamic and kinetic factors governing the oligomerization of four distinct peptide sequences (KFFE, KVVE, KLLE, KAAE).
• To correlate the early oligomerization thermodynamics with experimentally observed fibrillogenic propensities.
• To elucidate the role of sequence-specific interactions and conformational changes in peptide self-assembly.

Main Methods:

• Atomically detailed replica-exchange molecular dynamics (REMD) simulations were employed.
• Thermodynamic stability of peptide dimers was assessed via temperature of monomer association.
• Free energy landscapes of dimerization were calculated to analyze assembly pathways.

Main Results:

• Thermodynamic stability of dimers correlates with fibrillogenic potential; KFFE and KVVE dimers are more stable than KLLE and KAAE.
• Sequence-specific interpeptide interactions and configurational entropy changes influence dimer stability.
• KFFE exhibits downhill assembly kinetics, suggesting facile dimerization, while others face kinetic barriers.
• Dimeric states are heterogeneous, including beta-sheet structures and disordered intermediates.

Conclusions:

• Early oligomer thermodynamics, particularly dimer stability and assembly kinetics, effectively rationalize peptide fibrillogenic propensities.
• Sequence-dependent free energy landscapes dictate the accessibility of aggregation pathways.
• Understanding these early events is critical for predicting and controlling peptide self-assembly into fibrils.