(704e) Investigating Thermodynamics and Kinetics of a ?(16-22) Peptide Aggregation Using Coarse-Grained Simulations

Aβ(16-22) is an intrinsically disordered and amyloidogenic fragment of full length Aβ protein which is associated with Alzheimer’s disease. In the present study, we perform computer simulations of Aβ(16-22) peptide oligomerization and fibrillation by applying discontinuous molecular dynamics (DMD) simulation combined with an intermediate resolution protein model, PRIME20. We first construct a thermodynamics phase diagram of Aβ(16-22) peptide in the plane of temperature and concentration. The coexistence line between five types of peptide aggregates (native oligomer, disordered oligomer, 2-, 3- and 4-sheet fibrils) and the solution phase are determined by measuring the equilibrium soluble peptide concentration Ce(T) at which the peptide aggregate neither grows nor dissolves. The latent heat of soluble peptide aggregation into fibril is calculated by fitting lnCe-1/T data to the Van’t Hoff equation. The values are found to be close to the binding energy per peptide within the fibril. Next we investigate the effect of various degrees of supersaturation on cluster size and helix and β sheet content of the Aβ(16-22) aggregates formed at various temperatures and concentrations. The kinetically observed aggregates are structurally different from those predicted from the equilibrium phase diagram. In addition, we reveal the major energy barriers and intermediate structures along the Aβ(16-22) oligomerization (dimer to octamer) pathway by calculating the free energy profiles as a function of an optimized reaction coordinate.