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One of the principal hallmarks of Alzheimer’s disease (AD) is related to the aggregation of amyloid-β fibrils in an insoluble form in the brain, also known as amyloidosis. Therefore, a prominent therapeutic strategy against AD consists of either blocking the amyloid aggregation and/or destroying the already formed aggregates. Natural products have shown significant therapeutic potential as amyloid inhibitors from in vitro studies as well as in vivo animal tests. In this study, the interaction of five natural biophenols (curcumin, dopamine, (-)-epigallocatechin-3-gallate, quercetin, and rosmarinic acid) with amyloid-β(1–40) fibrils has been studied through computational simulations. The results allowed the identification and characterization of the different binding modalities of each compounds and their consequences on fibril dynamics and aggregation. It emerges that the lateral aggregation of the fibrils is strongly influenced by the intercalation of the ligands, which modulates the double-layered structure stability.

Increasing evidence suggests that amyloid polymorphism gives rise to different strains of amyloids with distinct toxicities and pathologyspreading properties. Validating this hypothesis is challenging due to a lack of tools and methods that allow for the direct characterization of amyloid polymorphism in hydrated and complex biological samples. Here, we report on the development of 11- mercapto-1-undecanesulfonate-coated gold nanoparticles (NPs) that efficiently label the edges of synthetic, recombinant, and native amyloid fibrils derived from different amyloidogenic proteins. We demonstrate that these NPs represent powerful tools for assessing amyloid morphological polymorphism, using cryogenic transmission electron microscopy (cryo-EM). The NPs allowed for the visualization of morphological features that are not directly observed using standard imaging techniques, including transmission electron microscopy with use of the negative stain or cryo-EM imaging. The use of these NPs to label native paired helical filaments (PHFs) from the postmortem brain of a patient with Alzheimer’s disease, as well as amyloid fibrils extracted from the heart tissue of a patient suffering from systemic amyloid light-chain amyloidosis, revealed a high degree of homogeneity across the fibrils derived from human tissue in comparison with fibrils aggregated in vitro. These findings are consistent with, and strongly support, the emerging view that the physiologic milieu is a key determinant of amyloid fibril strains. Together, these advances should not only facilitate the profiling and characterization of amyloids for structural studies by cryo-EM, but also pave the way to elucidate the structural basis of amyloid strains and toxicity, and possibly the correlation between the pathological and clinical heterogeneity of amyloid diseases.

We report a multi-scale simulation study of the photocycle of the rhodopsins. The quasi-atomistic representation (“united atoms” UA) of retinal is combined with a minimalist coarse grained (CG, one-bead-per amino acid) representation of the protein, in a hybrid UA/CG approach, which is the homolog of QM/MM, but at lower resolution. An accurate multi-stable parameterization of the model allows simulating each state and transition among them, and the combination of different scale representation allows addressing the entire photocycle. We test the model on bacterial rhodopsin, for which more experimental data are available, and then also report results for mammalian rhodopsins. In particular, the analysis of simulations reveals the spontaneous appearance of meta-stable states in quantitative agreement with experimental data.

Protein interactions with engineered gold nanoparticles (AuNPs) and the consequent formation of the protein corona are very relevant and poorly understood biological phenomena. The nanoparticle coverage affects protein binding modalities, and the adsorbed protein sites influence interactions with other macromolecules and cells. Here, we studied four common blood proteins, i.e., hemoglobin, serum albumin, α1-antiproteinase, and complement C3, interacting with AuNPs covered by hydrophobic 11-mercapto-1-undecanesulfonate (MUS). We use Molecular Dynamics and the Martini coarse−grained model to gain quantitative insight into the kinetics of the interaction, the physico-chemical characteristics of the binding site, and the nanoparticle adsorption capacity. Results show that proteins bind to MUS−capped AuNPs through strong hydrophobic interactions and that they adapt to the AuNP surfaces to maximize the contact surface, but no dramatic change in the secondary structure of the proteins is observed. We suggest a new method to calculate the maximum adsorption capacity of capped AuNPs based on the effective surface covered by each protein, which better represents the realistic behavior of these systems.

A multiscale molecular dynamics simulation study has been carried out in order to provide in-depth information on the adsorption of hemoglobin, myoglobin, and trypsin over citrate-capped AuNPs of 15 nm diameter. In particular, determinants for single proteins adsorption and simultaneous adsorption of the three types of proteins considered have been studied by Coarse-Grained and Meso-Scale molecular simulations, respectively. The results, discussed in the light of the controversial experimental data reported in the current experimental literature, have provided a detailed description of the (i) recognition process, (ii) number of proteins involved in the early stages of corona formation, (iii) protein competition for AuNP adsorption, (iv) interaction modalities between AuNP and protein binding sites, and (v) protein structural preservation and alteration.

Amyloid-β aggregation is one of the principal causes of amyloidogenic diseases that lead to the loss of neuronal cells and to cognitive impairments. The use of gold nanoparticles treating amyloidogenic diseases is a promising approach, because the chemistry of the gold surface can be tuned in order to have a specific binding, obtaining effective tools to control the aggregation. In this paper, we show, by means of Replica Exchange Solute Tempering Molecular Simulations, how electrostatic interactions drive the absorption of Amyloid-β monomers onto citrates-capped gold nanoparticles. Importantly, upon binding, amyloid monomers show a reduced propensity in forming β-sheets secondary structures that are characteristics of mature amyloid fibrils.

In this study, we compared the effects of two well-known natural compounds on the early step of the fibrillation process of amyloid-β (1–40), responsible for the formation of plaques in the brains of patients affected by Alzheimer’s disease (AD). The use of extensive replica exchange simulations up to the µs scale allowed us to characterize the inhibition activity of (–)-epigallocatechin-3-gallate (EGCG) and curcumin (CUR) on unfolded amyloid fibrils. A reduced number of β-strands, characteristic of amyloid fibrils, and an increased distance between the amino acids that are responsible for the intra- and interprotein aggregations are observed. The central core region of the amyloid-β (Aβ(1–40)) fibril is found to have a high affinity to EGCG and CUR due to the presence of hydrophobic residues. Lastly, the free binding energy computed using the Poisson Boltzmann Surface Ares suggests that EGCG is more likely to bind to unfolded Aβ(1–40) fibrils and that this molecule can be a good candidate to develop new and more effective congeners to treat AD.

Couroupita guianensis Aubl. is an important medicinal tree. This tree is rich in various phytochemicals, and is therefore used as a potent antioxidant and antibacterial agent. This plant is also used for the treatment of various diseases. Here, we have improved its medicinal usage with the biosynthesis of silver nanoparticles (AgNPs) using Couroupita guianensis Aubl. flower extract as a reducing and capping agent. The biosynthesis of the AgNPs reaction was carried out using 1 mM of silver nitrate and flower extract. The effect of the temperature on the biosynthesis of AgNPs was premeditated by room temperature (25 °C) and 60 °C. The continuous stirring of the reaction mixture at room temperature for approximately one hour resulted in the successful formation of AgNPs. A development of a yellowish brown color confirmed the formation of AgNPs. The efficacious development of AgNPs was confirmed by the characteristic peaks of UV–Vis, X-ray diffraction (XRD) and Fourier transform infrared (FT-IR) spectroscopy spectra. The biosynthesized AgNPs exhibited significant free radical scavenging activity through a DPPH antioxidant assay. These AgNPs also showed potent antibacterial activity against many pathogenic bacterial species. The results of molecular dynamics simulations also proved the average size of NPs and antibacterial potential of the flower extract. The observations clearly recommended that the green biosynthesized AgNPs can serve as effective antioxidants and antibacterial agents over the plant extract.

In the upcoming process to overcome the limitations of the standard von Neumann architecture, synaptic electronics is gaining a primary role for the development of in-memory computing. In this field, Ge-based compounds have been proposed as switching materials for nonvolatile memory devices and for selectors. By employing the classical molecular dynamics, we study the structural features of both the liquid states at 1500K and the amorphous phase at 300K of Ge-rich and Se-rich chalcogenides binary GexSe1-x systems in the range x 0.4-0.6. The simulations rely on a model of interatomic potentials where ions interact through steric repulsion, as well as Coulomb and charge-dipole interactions given by the large electronic polarizability of Se ions. Our results indicate the formation of temperature-dependent hierarchical structures with short-range local orders and medium-range structures, which vary with the Ge content. Our work demonstrates that nanosecond-long simulations, not accessible via ab initio techniques, are required to obtain a realistic amorphous phase from the melt. Our classical molecular dynamics simulations are able to describe the profound structural differences between the melt and the glassy structures of GeSe chalcogenides. These results open to the understanding of the interplay between chemical composition, atomic structure, and electrical properties in switching materials.

The misfolding and self-assembly of proteins into β-sheet-rich amyloid fibrils of various structures and morphologies is a hallmark of several neurodegenerative and systemic diseases. Increasing evidence suggests that amyloid polymorphism gives rise to different strains of amyloids with distinct toxicity and pathology-spreading properties. Validating this hypothesis is challenging due to a lack of tools and methods that allow for the direct characterization of amyloid polymorphism in hydrated and complex biological samples. Here, we report on the use of 11-mercapto-1-undecanesulfonate-coated gold nanoparticles (NPs) to label the edges of synthetic, recombinant and native amyloid fibrils to assess amyloid morphological polymorphism using cryogenic transmission electron microscopy (cryo TEM). The fibrils studied were derived from amyloid proteins involved in disorders of the central nervous system (amyloid-β, tau, α-synuclein) and in systemic amyloidosis (a fragment of an immunoglobulin light chain). The labeling efficiency enabled imaging and characterization of amyloid fibrils of different morphologies under hydrated conditions using cryo TEM. These NPs allowed for the visualization of morphological features that are not directly observed using standard imaging techniques, including TEM with use of the negative stain or cryo TEM imaging. We also demonstrate the use of these NPs to label native paired helical filaments (PHFs) from the postmortem brain of an Alzheimer's disease patient, as well as amyloid fibrils extracted from the heart tissue of a patient suffering from systemic amyloid light-chain (AL) amyloidosis. Analysis of the cryo TEM images of amyloids decorated with NPs shows exceptional homogeneity across the fibrils derived from human tissue in comparison to fibrils aggregated in vitro. The use of these NPs enabled us to gain novel insight into the structural features that distinguish amyloid fibrils formed in vivo from those formed in cell-free in vitro systems. Our findings demonstrate that these NPs represent a potent tool for rapid imaging and profiling of amyloid morphological polymorphism in different types of samples, including those derived from complex biological aggregates found in human tissue and animal models of amyloid diseases. This study should not only facilitate the profiling and characterization of amyloids for structural studies by cryo TEM but also pave the way to elucidate the structural basis of amyloid strains and toxicity and possibly the correlation between the pathological and clinical heterogeneity of amyloid diseases.