Computer Simulations of Alzheimers Amyloid β-Protein Folding and Assembly

Abstract

Pathological folding and aggregation of the amyloid -protein (A ) are widely perceived as central to understanding Alzheimer's disease (AD) at the molecular level. Experimental approaches to study A self-assembly are limited, because most relevant aggregates are quasi-stable and inhomogeneous. In contrast, simulations can provide significant insights into the problem, including specific sites in the molecule that would be attractive for drug targeting and details of the assembly pathways leading to the production of toxic assemblies. Here we review computer simulation approaches to understanding the structural biology of A . We discuss the ways in which these simulations help guide experimental work, and in turn, how experimental results guide the development of theoretical and simulation approaches that may be of general utility in understanding pathologic protein folding and assembly.

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

“…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 %.…”

“…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].…”

The Alzheimer β-amyloid (Aβ1–39) dimer in an implicit solvent

“…Currently, they are restricted to either aggregation of a small number of A␤ fragments such as three A␤ ͑16-22͒ peptides, 12 or stability studies of various A␤ dimers with predetermined structures. 18,19 Even with these limitations, all-atom MD simulations are confined to few microseconds, 20 while protein folding and aggregation occur on time scales larger than milliseconds. In order to overcome this limitation, we use an implicit solvent model which increases the efficiency of protein folding and aggregation studies by a factor of Ϸ10 7 compared to one utilizing an explicit solvent model.…”

The Role of Molecular Simulations in the Development of Inhibitors of Amyloid β-Peptide Aggregation for the Treatment of Alzheimer’s Disease

“…Given the difficulty in obtaining high-resolution structural information about Aβ and its aggregated states, MD simulations serve as an excellent tool for augmenting the current understanding of Aβ structure and dynamics. 30 MD simulations require a starting configuration of all of the molecules to be studied and a corresponding topology that describes the properties of each of the atoms. The dynamics are governed by potential energy functions that account for bonded interactions (bonds, angles, dihedrals, and planarity terms called "improper dihedrals") and nonbonded interactions (van der Waals interactions and electrostatics).…”