Computational Simulations of the Early Steps of Protein Aggregation

Abstract

There is strong evidence that the oligomers of key proteins, formed during the early steps of aggregation, could be the primary toxic species associated with human neurodegenerative diseases, such as Alzheimer's and prion diseases. Here, we review recent progress in the development of computational approaches in order to understand the structures, dynamics and free energy surfaces of oligomers. We also discuss possible research directions for the coming years.

Role of the Region 23-28 in Aβ Fibril Formation: Insights from Simulations of the Monomers and Dimers of Alzheimers Peptides Aβ40 and Aβ42

“…(21)(22)(23)(24)(25)(26)(27)(28)(29)(30). These include standard molecular dynamics (MD) [24], replica-exchange molecular dynamics (REMD) [25], discontinuous molecular dynamics (DMD) [26,27] and ART-OPEP [28].…”

“…Whether SC2-ART is an important basin remains to be determined, but the persistence of a loop at position 24-28 in the populated states is certainly responsible for the high stability of A! (21)(22)(23)(24)(25)(26)(27)(28)(29)(30) in solution. This is consistent with the REMD analysis [25].…”

“…An early study on the dimer of A! (16)(17)(18)(19)(20)(21)(22) shows very high similarity between the REMD-OPEP free energy surface and that generated by all-atom explicit solvent REMD simulations [22,68]. The REMD simulations are performed using 32 replicas between 290 and 650 K and running for 130 ns at each T. For the analysis, the first 30 ns are discarded and clustering is performed on the structures sampled at 300 K. Using a cut-off of 2.5 Å, the 5566 structures are classified into 85 clusters, with the largest 20 representing 83 % of the ensemble and probabilities varying between 10 and 1 %.…”

“…(21)(22)(23)(24)(25)(26)(27)(28)(29)(30), and the monomers and dimers of A!40 and A!42. In particular, we focus on whether the formation of a loop in the region 21-30 is the rate-limiting step in A!…”

“…Reviews on the use of simulations to understand protein aggregation in general and the assembly of small amyloid-forming peptides A! can be found elsewhere [15,[18][19][20][21][22].…”