Effects of ion type and concentration on the structure and aggregation of the amyloid peptide A ß 16 - 22 $$ {\boldsymbol{\beta}}_{16-22} $$.

Among the various factors controlling the amyloid aggregation process, the influences of ions on the aggregation rate and the resulting structures are important aspects to consider, which can be studied by molecular simulations. There is a wide variety of protein force fields and ion models, raising the question of which model to use in such studies. To address this question, we perform molecular dynamics simulations of Aß16-22 , a fragment of the Alzheimer's amyloid ß peptide, using different protein force fields, AMBER99SB-disp (A99-d) and CHARMM36m (C36m), and different ion parameters. The influences of NaCl and CaCl2 at various concentrations are studied and compared with the systems without the addition of ions. Our results indicate a sensitivity of the peptide-ion interactions to the different ion models. In particular, we observe a strong binding of Ca2+ to residue E22 with C36m and also with the Åqvist ion model used together with A99-d, which slightly affects the monomeric Aß16-22 structures and the aggregation rate, but significantly affects the oligomer structures formed in the aggregation simulations. For example, at high Ca2+ concentrations, there was a switch from an antiparallel to a parallel ß-sheet. Such ionic influences are of biological relevance because local ion concentrations can change in vivo and could help explain the polymorphism of amyloid fibrils.

Structural Dissection of the First Events Following Membrane Binding of the Islet Amyloid Polypeptide.

The islet amyloid polypeptide (IAPP) is the main constituent of the amyloid fibrils found in the pancreas of type 2 diabetes patients. The aggregation of IAPP is known to cause cell death, where the cell membrane plays a dual role: being a catalyst of IAPP aggregation and being the target of IAPP toxicity. Using ATR-FTIR spectroscopy, transmission electron microscopy, and molecular dynamics simulations we investigate the very first molecular steps following IAPP binding to a lipid membrane. In particular, we assess the combined effects of the charge state of amino-acid residue 18 and the IAPP-membrane interactions on the structures of monomeric and aggregated IAPP. Distinct IAPP-membrane interaction modes for the various IAPP variants are revealed. Membrane binding causes IAPP to fold into an amphipathic α-helix, which in the case of H18K-, and H18R-IAPP readily moves beyond the headgroup region. For all IAPP variants but H18E-IAPP, the membrane-bound helix is an intermediate on the way to amyloid aggregation, while H18E-IAPP remains in a stable helical conformation. The fibrillar aggregates of wild-type IAPP and H18K-IAPP are dominated by an antiparallel ß-sheet conformation, while H18R- and H18A-IAPP exhibit both antiparallel and parallel ß-sheets as well as amorphous aggregates. Our results emphasize the decisive role of residue 18 for the structure and membrane interaction of IAPP. This residue is thus a good therapeutic target for destabilizing membrane-bound IAPP fibrils to inhibit their toxic actions.

Disorder-to-order transition of the amyloid-ß peptide upon lipid binding.

There is mounting evidence that Alzheimer's disease progression and severity are linked to neuronal membrane damage caused by aggregates of the amyloid-ß (Aß) peptide. However, the detailed mechanism behind the membrane damage is not well understood yet. Recently, the lipid-chaperone hypothesis has been put forward, based on which the formation of complexes between Aß and free lipids enables an easy insertion of Aß into membranes. In order to test this hypothesis, we performed numerous all-atom molecular dynamics simulations. We studied the complex formation between individual lipids, considering both POPC and DPPC, and Aß and examined whether the resulting complexes would be able to insert into lipid membranes. Complex formation at a one-to-one ratio was readily observed, yet with minimal effects on Aß's characteristics. Most importantly, the peptide remains largely disordered in 1:1 complexes, and the complex does not insert into the membrane; instead, it is adsorbed to the membrane surface. The results change considerably once Aß forms a complex with a POPC cluster composed of three lipid molecules. The hydrophobic interactions between Aß and the lipid tails cause the peptide to fold into either a helical or a ß-sheet structure. These observations provide atomic insight into the disorder-to-order transition that is needed for membrane insertion or amyloid aggregation to proceed.

Molecular simulations of IDPs: From ensemble generation to IDP interactions leading to disorder-to-order transitions.

Intrinsically disordered proteins (IDPs) lack a well-defined three-dimensional structure but do exhibit some dynamical and structural ordering. The structural plasticity of IDPs indicates that entropy-driven motions are crucial for their function. Many IDPs undergo function-related disorder-to-order transitions upon by their interaction with specific binding partners. Approaches that are based on both experimental and theoretical tools enable the biophysical characterization of IDPs. Molecular simulations provide insights into IDP structural ensembles and disorder-to-order transition mechanisms. However, such studies depend strongly on the chosen force field parameters and simulation techniques. In this chapter, we provide an overview of IDP characteristics, review all-atom force fields recently developed for IDPs, and present molecular dynamics-based simulation methods that allow IDP ensemble generation as well as the characterization of disorder-to-order transitions. In particular, we introduce metadynamics, replica exchange molecular dynamics simulations, and also kinetic models resulting from Markov State modeling, and provide various examples for the successful application of these simulation methods to IDPs.

Amyloid-ß peptide dimers undergo a random coil to ß-sheet transition in the aqueous phase but not at the neuronal membrane.

Mounting evidence suggests that the neuronal cell membrane is the main site of oligomer-mediated neuronal toxicity of amyloid-ß peptides in Alzheimer's disease. To gain a detailed understanding of the mutual interference of amyloid-ß oligomers and the neuronal membrane, we carried out microseconds of all-atom molecular dynamics (MD) simulations on the dimerization of amyloid-ß (Aß)42 in the aqueous phase and in the presence of a lipid bilayer mimicking the in vivo composition of neuronal membranes. The dimerization in solution is characterized by a random coil to ß-sheet transition that seems on pathway to amyloid aggregation, while the interactions with the neuronal membrane decrease the order of the Aß42 dimer by attenuating its propensity to form a ß-sheet structure. The main lipid interaction partners of Aß42 are the surface-exposed sugar groups of the gangliosides GM1. As the neurotoxic activity of amyloid oligomers increases with oligomer order, these results suggest that GM1 is neuroprotective against Aß-mediated toxicity.

Role of Oxidized Gly25, Gly29, and Gly33 Residues on the Interactions of Aß1-42 with Lipid Membranes.

Oxidative stress is known to play an important role in the pathogenesis of Alzheimer's disease. Moreover, it is becoming increasingly evident that the plasma membrane of neurons plays a role in modulating the aggregation and toxicity of Alzheimer's amyloid-ß peptide (Aß). In this study, the combined and interdependent effects of oxidation and membrane interactions on the 42 residues long Aß isoform are investigated using molecular simulations. Hamiltonian replica exchange molecular dynamics simulations are utilized to elucidate the impact of selected oxidized glycine residues of Aß42 on the interactions of the peptide with a model membrane comprised of 70% POPC, 25% cholesterol, and 5% of the ganglioside GM1. The main findings are that, independent of the oxidation state, Aß prefers binding to GM1 over POPC, which is further enhanced by the oxidation of Gly29 and Gly33 and reduced the formation of ß-sheet. Our results suggest that the differences observed in Aß42 conformations and its interaction with a lipid bilayer upon oxidation originate from the position of the oxidized Gly residue with respect to the hydrophobic sequence of Aß42 involving the Gly29-XXX-Gly33-XXX-Gly37 motif and from specific interactions between the peptide and the terminal sugar groups of GM1.