Aggregation of the natively unfolded protein α-synuclein (α-syn) is key to the development of Parkinson’s disease (PD). Some nanoparticles (NPs) can inhibit this process and in turn be used for treatment of PD. Using simulation strategies, we show here that α-syn self-assembly is electrostatically driven. Dimerization by head-to-head monomer contact is triggered by dipole–dipole interactions and subsequently stabilized by van der Waals interactions and hydrogen bonds. Therefore, we hypothesized that charged nano-objects could interfere with this process and thus prevent α-syn fibrillation. In our simulations, positively and negatively charged graphene sheets or superparamagnetic iron oxide NPs first interacted with α-syn’s N/C terminally charged residues and then with hydrophobic residues in the non-amyloid-β component (61–95) region. In the experimental setup, we demonstrated that the charged nano-objects have the capacity not only to strongly inhibit α-syn fibrillation (both nucleation and elongation) but also to disaggregate the mature fibrils. Through the α-syn fibrillation process, the charged nano-objects induced the formation of off-pathway oligomers.

Once in biological fluids, the surface of nanoparticles (NPs) is rapidly covered with a layer of biomolecules (i.e., the "protein corona") whose composition strongly determines their biological identity, regulates interactions with biological entities including cells and the immune system, and consequently directs the biological fate and pharmacokinetics of nanoparticles. We recently introduced the concept of a "personalized protein corona" which refers to the formation of different biological identities of the exact same type of NP after being exposed to extract plasmas from individuals who have various types of diseases. As different diseases have distinct metabolomic profiles and metabolites can interact with proteins, it is legitimate to hypothesize that metabolomic profiles in plasma may have the capacity to, at least partially, drive the formation of a personalized protein corona. To test this hypothesis, we employed a multi-scale approach composed of coarse-grained (CG) and all atom (AA) molecular dynamics (MD) simulations to probe the role of glucose and cholesterol (model metabolites in diabetes and hypercholesterolemia patients) in the interaction of fibrinogen protein and polystyrene NPs. Our results revealed that glucose and cholesterol had the capacity to induce substantial changes in the binding site of fibrinogen to the surface of NPs. More specifically, the simulation results demonstrated that increasing the metabolite amount could change the profiles of fibrinogen adsorption and replacement, what is known as the Vroman effect, on the NP surface. In addition, we also found out that metabolites can substantially determine the immune triggering potency of the fibrinogen-NP complex. Our proof-of-concept outcomes further emphasize the need for the development of patient-specific NPs in a disease type-specific manner for high yielding and safe clinical applications.

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Mineralized collagen fibrils (MCFs) comprise collagen molecules and hydroxyapatite (HAp) crystals and are considered universal building blocks of bone tissue, across different bone types and species. In this study, we developed a coarse-grained molecular dynamics (CGMD) framework to investigate the role of mineral arrangement on the load-deformation behaviour of MCFs. Despite the common belief that the collagen molecules are responsible for flexibility and HAp minerals are responsible for stiffness, our results showed that the mineral phase was responsible for limiting collagen sliding in the large deformation regime, which helped the collagen molecules themselves undergo high tensile loading, providing a substantial contribution to the ultimate tensile strength of MCFs. This study also highlights different roles for the mineralized and non-mineralized protofibrils within the MCF, with the mineralized groups being primarily responsible for load carrying due to the presence of the mineral phase, while the non-mineralized groups are responsible for crack deflection. These results provide novel insight into the load-deformation behaviour of MCFs and highlight the intricate role that both collagen and mineral components have in dictating higher scale bone biomechanics.

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