Parkinson’s disease (PD) is characterized by a progressive loss of dopaminergic neurons, a process that current therapeutic approaches cannot prevent. In PD, the typical pathological hallmark is the accumulation of intracellular protein inclusions, known as Lewy bodies and Lewy neurites, which are mainly composed of α-synuclein. Here, we exploited a high-throughput screening methodology to identify a small molecule (SynuClean-D) able to inhibit α-synuclein aggregation. SynuClean-D significantly reduces the in vitro aggregation of wild-type α-synuclein and the familiar A30P and H50Q variants in a substoichiometric molar ratio. This compound prevents fibril propagation in protein-misfolding cyclic amplification assays and decreases the number of α-synuclein inclusions in human neuroglioma cells. Computational analysis suggests that SynuClean-D can bind to cavities in mature α-synuclein fibrils and, indeed, it displays a strong fibril disaggregation activity. The treatment with SynuClean-D of two PD Caenorhabditis elegans models, expressing α-synuclein either in muscle or in dopaminergic neurons, significantly reduces the toxicity exerted by α-synuclein. SynuClean-D–treated worms show decreased α-synuclein aggregation in muscle and a concomitant motility recovery. More importantly, this compound is able to rescue dopaminergic neurons from α-synuclein–induced degeneration. Overall, SynuClean-D appears to be a promising molecule for therapeutic intervention in Parkinson’s disease.

The NonCovalent Interaction index (NCI) enables identification of attractive and repulsive noncovalent interactions from promolecular densities in a fast manner. However, the approach remained up to now qualitative, only providing visual information. We present a new version of NCIPLOT, NCIPLOT4, which allows quantifying the properties of the NCI regions (volume, charge) in small and big systems in a fast manner. Examples are provided of how this new twist enables characterization and retrieval of local information in supramolecular chemistry and biosystems at the static and dynamic levels.

The glycan structures of the receptor binding domain of the SARS‐CoV2 spike glycoprotein expressed in human HEK293F cells have been studied by using NMR. The different possible interacting epitopes have been deeply analysed and characterized, providing evidence of the presence of glycan structures not found in previous MS‐based analyses. The interaction of the RBD 13C‐labelled glycans with different human lectins, which are expressed in different organs and tissues that may be affected during the infection process, has also been evaluated by NMR. In particular, 15N‐labelled galectins (galectins‐3, ‐7 and ‐8 N‐terminal), Siglecs (Siglec‐8, Siglec‐10), and C‐type lectins (DC‐SIGN, MGL) have been employed. Complementary experiments from the glycoprotein perspective or from the lectin's point of view have permitted to disentangle the specific interacting epitopes in each case. Based on these findings, 3D models of the interacting complexes have been proposed.

Noncovalent interactions are of utmost importance. However, their accurate treatment is still difficult. This is partially induced by the coexistence of many types of interactions and physical phenomena, which hampers generality in simple treatments. The NCI index has been successfully used for nearly over 10 years in order to identify, analyze, and understand noncovalent interactions in a wide variety of systems, ranging from proteins to molecular crystals. In this work, the development and implications of the method will be reviewed, and modern implementations will be presented. Afterward, some sophisticated examples will be given that showcase the current advances toward the fast, robust, and intuitive identification of noncovalent interactions in real space. This article is categorized under: Software > Molecular Modeling Quantum Computing > Theory Development Structure and Mechanism > Computational Biochemistry and Biophysics

There is an increasing interest in synthetic systems that can execute bio-inspired chemical reactions without requiring the complex structures that characterize enzymes in their components.The hierarchical self-assembly of peptides provides a means to create catalytic microenvironments. Ideally, as it occurs in enzymes, the catalytic activity of peptide nanostructures should be reversibly regulated. In a typical enzyme mimetic design, the peptide's self-assembling and catalytic activities are segregated into different regions of the sequence. Here, we aimed to design minimal peptides in which the self-assembly and function were all encoded in the same amino acids. Moreover, we wanted to endorse the resulting one-component nanomaterial with divergent, chemically unrelated, catalytic activities, a property not observed in natural enzymes. We show that short peptides consisting only of histidine and tyrosine residues, arranged in a binary pattern, form biocompatible amyloid-like fibrils and hydrogels combining hydrolytic and electrocatalytic activities. The nanofibers' mesoscopic properties are controlled by pH, the transition between assembled active b-sheet fibrils, and disassembled inactive random coil species occurring in a physiologically relevant pH range. The structure of one of such amyloid-like fibrils, as derived from molecular dynamic simulations, provides insights on how they attain this unique combination of structural and catalytic properties.

Alzheimer's disease is a challenge of the utmost importance for contemporary society. An early diagnosis is essential for the development of treatments and for establishing a network of support for the patient. In this light, the deposition in the brain of amyloid-β fibrillar aggregates, which is a distinctive feature of Alzheimer, is key for an early detection of this disease. In this work we propose an atomistic study of the interaction of amyloid tracers with recently published polymorphic models of amyloid-β 1-40 and 1-42 fibrils, highlighting the relationship between marker architectures and binding affinity. This work uncovers the importance of quaternary structure, and in particular of junctions between amyloid-β protofilaments, as the key areas for marker binding.

The main hallmark of Alzheimer's disease is the deposition of amyloid-β (Aβ) aggregates in the brain. An early diagnosis of the disease requires a fast and accurate detection of such aggregates in vivo. NIAD-4 is one of the most promising in vivo markers developed due to its high emission at λ > 600 nm and its ability to rapidly cross the blood-brain barrier (BBB) and target Aβ deposits. Furthermore, it shows a dramatic fluorescence enhancement upon binding to amyloid fibrils, which is essential for attaining good imaging contrast. Aiming at establishing novel design concepts for the preparation of optimized optical probes, the current work rationalizes the excellent performance of NIAD-4 by using a pool of computational (TD-DFT and CASPT2 calculations, ab initio molecular dynamics and protein energy landscape exploration) and spectroscopic techniques. Unlike other markers operating as molecular rotors or polarity-sensitive dyes, we uncover herein that the high fluorescence imaging contrast observed upon NIAD-4 binding to amyloid fibrils results from reversible aggregation. NIAD-4 forms non-emissive assemblies in aqueous solution already at very low concentrations, which convert into the highly fluorescent monomeric species by diffusion into the hydrophobic voids of Aβ deposits. This result paves the way to exploit aggregation-induced processes as a new strategy towards advanced fluorescence markers for amyloid detection.

Carbonate apatite is a material of the utmost importance as it represents the inorganic fraction of biological hard tissues in bones and teeth. Here we study the static and dynamic features of CO3 2– ion in the apatitic channel of carbonate apatite (A-type substitution), by applying both static and dynamic quantum mechanical calculations based on density functional methods with B3LYP-D* and PBE functionals. The static calculations reveal a number of almost energetically equivalent carbonate configurations in the channel, leading to cell parameters compatible with the P 3̅ space group assigned by the experimental X-ray structure determination. Ab initio isothermal–isobaric molecular dynamics simulations provide insights on the CO3 2– mobility, showing that at the temperature of the experimental structural determination the CO3 2– moiety undergoes a dynamic disorder, as the carbonate group is almost free to move within the apatitic channel enhancing its exchangeability with other anions.