Increasing evidence suggests that amyloid polymorphism gives rise to different strains of amyloids with distinct toxicities 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 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.
The bacterium strain Ideonella sakaiensis 201‐F6 is able to hydrolyze low‐crystallinity PET films at 30 °C due to two enzymes named PETase and MHETase. Since its discovery, many efforts have been dedicated to elucidating the structure and features of those two enzymes, and various authors have highlighted the necessity to optimize both the substrate binding site and the global structure in order to enhance the stability and catalytic activity of these PET biocatalysts so as to make them more suitable for industrial applications. In this review, the strategies adopted by different research groups to investigate the structure and functionality of both PETase and MHETase in depth are described, emphasizing the advantages provided by the use of computational methods to complement and drive experiments. Subsequently, the modifications implemented with protein engineering are discussed. The versatility of the enzymes secreted by I. sakaiensis enables the prediction that they will find several applications in the disposal of PET debris, encouraging a prioritization of efforts in this prolific research field.
The comprehension of the nonlinear effects provided by mixed alkali effect (MAE) in oxide glasses is useful to optimize glass compositions to achieve specific properties that depend on the mobility of ions, such as the chemical durability, glass transition temperature, viscosity and ionic conductivity. Although molecular dynamics (MD) simulations have already been applied to investigate the MAE on silicates, less effort has been devoted to study such phenomenon in mixed alkali aluminosilicate glasses where alkali cations can act both as modifiers, forming non-bridging oxygens and percolation channels, and as charge compensator of the Alo 4 − units present in the network. Moreover, the ionic conductivity has not been computed yet; thus, the accuracy of the atomistic simulations in reproducing the MAE on the property is still open to question. In this work, we have validated five major interatomic potentials for the classical MD simulations by modelling the structure, density, glass transition temperature and ionic conductivity for three aluminosilicate glasses, (25 − x)Na 2 o − x(K 2 O) − 10(Al 2 o 3) − 65(SiO 2) (x = 0, 12.5, 25). It was observed that only the core-shell (CS) polarizable force field well reproduces the experimentally measured MAe on T g and the ionic conductivity as well as the higher conductivity of single sodium aluminosilicate glass at low temperature and the higher conductivity of single potassium aluminosilicate glass at high temperature. The MAE is related to the suppression of jump events of the alkaline ions between dissimilar sites in the percolation channels consisting of both sodium and potassium ions as in the case of alkaline silicates. The superior reproducibility of the CS potential is originated from the larger and the flexible ring structures due to the smaller Si-O-Si inter-tetrahedra angle, creating appropriate percolation channels for ion conductivity. We also report detailed assessments for using the potential models including the CS potential for investigating MAE on aluminosilicates. Ionic conductivity in inorganic glasses is gaining a huge interest for the enormous number of applications that such materials are having in a number of major technological developments in the domains of energy conversion and storage (solid electrolytes in battery and fuel cells) or in the environmental monitoring (solid state ionic membranes for sensors) 1. Among the various ways to control ionic diffusion and thus ionic conductivity a possibility is that to exploit the so-called Mixed Alkali Effect (MAE) or more in general the Mixed Ion Effect (MIE) 2,3. This effect refers to a large non-linear deviation in glass properties observed when an alkali cation (or more in general a mobile ion) is gradually replaced by another alkali cation. The ionic conductivity of glasses exhibiting the MAE shows a deep minimum when half of the alkaline ions of type A are replaced by type B ions, meaning that cation mobility progressively reduces up to a substitution ratio equal to unity. The minimum is more pron...
widely used for the simulation of a large variety of silicates, aluminosilicate and phosphate crystals, and multicomponent oxide glasses have been revised and improved by the inclusion of two types of three-body interactions acting between T-O-T bridges (T = Si and P) and network former-network former repulsive interactions. The FFs named Bertani-Menziani-Pedone (BMP)-harm and BMP-shrm better reproduce the T-O-T bond angle distributions (BADs) and network former-oxygen distances. Consequently, the prediction of Q n distributions (Q stands for quaternary species, and n is the number of bridging oxygens around it), neutron total distribution functions, solid-state nuclear magnetic resonance spectra of spin active nuclei ( 29 Si, 17 O, 31 P, 27 Al), and the density have also been hugely improved with respect to the previous version of our FF. These results also highlight the strong correlation between the T-O-T BADs and the other short and intermediate structural properties in oxide glasses, which have been largely neglected in the past. In addition to the improvement of the structure, the FF has been revealed to reproduce well the ionic conductivity in mixed alkali aluminosilicate glasses and the elastic properties. The systematic comparison with other interatomic potential models, including the polarizable core-shell model, carried out in this paper showed that our potential model is more balanced and effective for simulating a vast family of crystalline and amorphous oxide-based 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.
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