Non-Amyloid‑β Component of Human α‑Synuclein Oligomers Induces Formation of New Aβ Oligomers: Insight into the Mechanisms That Link Parkinson’s and Alzheimer’s Diseases

Parkinson’s disease (PD) is characterized by the formation of Lewy bodies (LBs), of which their major component is the non-amyloid-β component (NAC) of α-synuclein (AS). Clinical studies have identified a link between PD and Alzheimer’s disease (AD), but the question of why PD patients are at risk to develop various types of dementia, such as AD, is still elusive. <i>In vivo</i> studies have shown that Aβ can act as a seed for NAC/AS aggregation, promoting NAC/AS aggregation and thus contributing to the etiology of PD. However, the mechanisms by which NAC/AS oligomers interact with Aβ oligomers are still elusive. This work presents the interactions between NAC oligomers and Aβ oligomers at atomic resolution by applying extensive molecular dynamics simulations for an ensemble of cross-seeded NAC–Aβ_1–42 oligomers. The main conclusions of this study are as follows: first, the cross-seeded NAC–Aβ_1–42 oligomers represent polymorphic states, yet NAC oligomers prefer to interact with Aβ_1–42 oligomers to form double-layer over single-layer conformations due to electrostatic/hydrophobic interactions; second, among the single-layer conformations, the NAC oligomers induce formation of new β-strands in Aβ_1–42 oligomers, thus leading to new Aβ oligomer structures; and third, NAC oligomers stabilize the cross-β structure of Aβ oligomers, i.e., yielding compact Aβ fibril-like structures

Molecular Mechanisms of the Bindings between Non-Amyloid β Component Oligomers and Amylin Oligomers

It has been suggested that the connection between amyloidogenic diseases is related to the interactions between aggregates of amyloids, which are related to type 2 diabetes and Parkinson’s disease. Herein, we illustrate the interactions between amylin oligomers and non-amyloid β component (NAC) oligomers. Using molecular dynamics simulations and statistical calculations, we studied the mechanisms through which NAC oligomers interact with amylin oligomers to form NAC–amylin hetero-oligomers. Our simulations have shown that there are more than one possible pathways, which form the NAC–amylin hetero-oligomers. Our structural analyses demonstrate that the interactions in the NAC–amylin hetero-oligomers do not affect the structural features of the NAC oligomers, but they do stabilize the structures of the amylin oligomers. Taken together, our results strongly support the hypothesis that NAC oligomers may interact with amylin oligomers through several pathways, of which some pathways are more preferred because of the structural stability of the cross-seeding NAC–amylin oligomers

Parameterization of Palmitoylated Cysteine, Farnesylated Cysteine, Geranylgeranylated Cysteine, and Myristoylated Glycine for the Martini Force Field

Peripheral membrane proteins go through various post-translational modifications that covalently bind fatty acid tails to specific amino acids. These post-translational modifications significantly alter the lipophilicity of the modified proteins and allow them to anchor to biological membranes. Over 1000 different proteins have been identified to date that require such membrane–protein interactions to carry out their biological functions, including members of the Src and Ras superfamilies that play key roles in cell signaling and carcinogenesis. We have used all-atom simulations with the CHARMM36 force field to parameterize four of the most common post-translational modifications for the Martini 2.2 force field: palmitoylated cysteine, farnesylated cysteine, geranylgeranylated cysteine, and myristoylated glycine. The parameters reproduce the key features of clusters of configurations of the different anchors in lipid membranes as well as the water–octanol partitioning free energies of the anchors, which are crucial for the correct reproduction of the expected biophysical behavior of peripheral membrane proteins at the membrane–water interface. Implementation in existing Martini setup tools facilitates the use of the new parameters

Orientations of Residues along the β‑Arch of Self-Assembled Amylin Fibril-Like Structures Lead to Polymorphism

Amylin is an endocrine hormone peptide that consists of 37 residues and is the main component of extracellular amyloid deposits found in the pancreas of most type 2 diabetes patients. Amylin peptides are self-assembled to form oligomers and fibrils. So far, four different molecular structures of the self-assembled amylin fibrils have been observed experimentally: two ssNMR models and two crystal models. This study reveals, for the first time, that there are four self-assembled amylin forms that differ in the orientations of the side chains along the β-arch and are all derived from the two ssNMR models. The two ssNMR models are composed of these four different self-assembled forms of amylin, and the two crystal models are composed of two different self-assembled forms of amylin. This study illustrates at the atomic level the differences among the four experimental models and proposes eight new models of self-assembled amylin that are also composed of the four different self-assembled forms of amylin. Our results show polymorphism of the self-assembled fibril-like amylin, with a slight preference of some of the newly constructed models over the experimental models. Finally, we propose that two different self-assembled fibril-like forms of amylin can interact to form a new fibril-like amylin. We investigated this argument and found that some fibril-like amylin prefers to interact to form stable fibril-like structures, whereas others disfavor it. Our work provides new insights that may suggest strategies for future pharmacological studies that aim to find ways to ameliorate the interactions between polymorphic oligomers and fibrils of amylin

Spontaneous Structural Transition in Phospholipid-Inspired Aromatic Phosphopeptide Nanostructures

Phospholipid membranes could be considered a prime example of the ability of nature to produce complex yet ordered structures, by spontaneous and efficient self-assembly. Inspired by the unique properties and architecture of phospholipids, we designed simple amphiphilic decapeptides, intended to fold in the center of the peptide sequence, with a phosphorylated serine “head” located within a central turn segment, and two hydrophobic “tails”. The molecular design also included the integration of the diphenylalanine motif, previously shown to facilitate self-assembly and increase nanostructure stability. Secondary structure analysis of the peptides indeed indicated the presence of stabilized conformations in solution, with a central turn connecting two hydrophobic “tails”, and interactions between the hydrophobic strands. The mechanisms of assembly into supramolecular structures involved structural transitions between different morphologies, which occurred over several hours, leading to the formation of distinctive nanostructures, including half-elliptical nanosheets and curved tapes. The phosphopeptide building blocks appear to self-assemble <i>via</i> a particular combination of aromatic, hydrophobic and ionic interactions, as well as hydrogen bonding, as demonstrated by proposed constructed simulated models of the peptides and self-assembled nanostructures. Molecular dynamics simulations also gave insight into mechanisms of structural transitions of the nanostructures at a molecular level. Because of the biocompatibility of peptides, the phosphopeptide assemblies allow for expansion of the library of biomolecular nanostructures available for future design and application of biomedical devices