Free energy landscapes for amyloidogenic tetrapeptides dimerization.

The oligomerization of four peptide sequences, KFFE, KVVE, KLLE, and KAAE is studied using replica-exchange molecular dynamics simulations with an atomically detailed peptide model. Previous experimental studies reported that of these four peptides, only those containing phenylalanine and valine residues form fibrils. We show that the fibrillogenic propensities of these peptides can be rationalized in terms of the equilibrium thermodynamics of their early oligomers. Thermodynamic stability of dimers, as measured by the temperature of monomer association, is seen to be higher for those peptides that are able to form fibrils. Although the relative high and low stabilities of the KFFE and KAAE dimers arise from their respective high and low interpeptide interaction energies, the higher stability of the KVVE dimer over the KLLE system results from the smaller loss of configurational entropy accompanying the dimerization of KVVE. Free energy landscapes for dimerization are found to be strongly sequence-dependent, with a high free energy barrier separating the monomeric and dimeric states for KVVE, KLLE, and KAAE sequences. In contrast, the most fibrillogenic peptide, KFFE, displayed downhill assembly, indicating enhanced kinetic accessibility of its dimeric states. The dimeric phase for all peptide sequences is found to be heterogeneous, containing both antiparallel beta-sheet structures that can grow into full fibrils as well as disordered dimers acting as on- or off-pathway intermediates for fibrillation.