Molecular Simulations and Alzheimer׳s Disease

Alzheimer׳s Disease (AD) is a progressive neurodegenerative disorder that represents a major threat to public health. A key player in AD is the short peptide Amyloid-β (Aβ), which forms soluble oligomers, structured filaments and fibrils, and finally plaques in patients’ brains. A rational design of anti-aggregation drugs requires knowledge of the target molecular structure, which is difficult to be obtained by experimental methods due to the multitude of Aβ aggregation states and conformations. In this context, computer simulation methods like molecular dynamics (MD) simulations offer a valuable supplement.

The present article gives a brief introduction into the structure of Aβ aggregates and the principles of MD simulations. The application of MD simulations in AD is illustrated by several sample cases from the authors’ research area, in which MD simulations are used to assess the effects of various intrinsic and extrinsic factors on the conformational stability of Aβ aggregates. In particular, the role of the following factors on Aβ structure are discussed (i) influence of aggregate size and topology, (ii) influence of familial and designed point mutations, (iii) role of the N- and C-terminus for fibril and oligomer stability, (iv) differential effects of the alkali metal ions Li⁺, Na⁺, and K⁺ (v) mechanism of small-molecule aggregation modulators. These studies demonstrate that MD simulations cannot only be used to gain a deeper mechanistic understanding of Aβ aggregation but may also support the rational design of anti-aggregation compounds.