Protein misfolding has long been known to constitute an important class of disease initiating factors. Of special significance in this group is Alzheimers disease (AD) in which the aggregation of misfolded small molecular weight amyloid ß peptides (Aß) triggers a host of biochemical anomalies that destroy brain neuronal processes. However, in spite of the enormous efforts invested into AD research over the past one century, it has remained without a cure. The available drugs only offer symptomatic relief without improving the associated neurological decline and the typically poor prognosis. The absence of a cure largely results from the peculiarities of the Aß peptide, the molecular principle commonly targeted for drug development. Aß is produced via post-translational cleavage of the transmembrane amyloid precursor protein followed by its release into the extracellular medium. Unlike most other protein drug targets however, Aß both lacks a regular three dimensional fold and possesses a significantly high aggregation propensity under physiological conditions. Aß’s extremely high aggregation tendency renders most available experimental structure determination tools, to a large extent, unable to determine its physiological conformations. Attempts to address this challenge includes the use of nonphysiological solubilising conditions, which at the same time compromises the usefulness of such models for Aß-directed drug discovery. Molecular simulations provide a veritable tool for circumventing this challenge and have been employed in this thesis. In this thesis, a number of molecular simulation techniques have been employed in studying and describing the structural dynamics of the two physiologically dominant Aß species–Aß40 and Aß42. Multiple molecular dynamics (MD) simulations on microsecond time scale were used to study Aß40 and Aß42 monomers in explicit water and under simulation conditions mimicking physiological conditions. To validate the obtained results, we employed chemical shift calculations which we compared with Nuclear Magnetic Resonance (NMR) chemical shifts, enabling us identify the force field that correctly models experimentally relevant Aß structural ensembles. We observed Aß42 monomer to form higher ß-sheet structure than Aß40 and provided an explanation for this and other specific aspects of the folding. We also employed atomistic MD simulation in studying the conformational behaviour of Aß42 monomer under four pH conditions and found the peptide net charge to be the single most important factor directing its folding. Our goal for analysing Aß’s conformation is to obtain structural ensembles closely resembling the physiological state, which can be used in investigating Aβ’s interaction with aggregation inhibitors (D-peptides) currently investigated in the group of Prof. Dr. Willbold (Institute of Complex Systems Forschungszentrum, Jülich) for their anti-amyloid activities against Aß. The inhibitors abolished Aß’s toxicity in a dose-dependent manner, but their mechanism(s) of action, to a large extent, remains unknown. In this work, we present the outcome of the molecular simulations performed to explain the possible mechanism of action of the D-peptides. Our analyses reveal the D-peptides as interacting with both Aß42 monomer and pentamer via strong electrostatic attraction and destroying its ß-sheets. We also performed exhaustive point mutations on the D-peptides’ sequences using both natural and non-natural amino acids. Our results suggest possible modifications that may be performed on the original D-peptides’ amino acid sequences that can help modify their selectivity for different Aß oligomer sizes. Based on these results we propose possible changes to the original D-peptide sequences, and their binding selectivity for different Aß oligomer will be tested in future experiments
