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Transition metals directly contribute to the neurotoxicity of the aggregates of the amyloid-forming A$\beta$ peptide. The understanding and rationalisation of the coordination modes of metals to A$\beta$ amyloid is therefore of paramount importance to understand the capacity of a given metal to promote peptide aggregation. Experimentally, multiple A$\beta$-metal structures have been resolved, which exhibit different modes of coordination in both the monomeric and oligomeric forms of A$\beta$. Although Zn(II) metalloproteins are very abundant and often involve cysteine residues in the first coordination shell, in the case of A$\beta$-Zn(II), though, Zn(II) is coordinated by glutamic/aspartic acid and/or histidine residues exclusively, making for an interesting case study. Here we present a systematic analysis on the underlying chemistry on A$\beta$- Zn(II) coordination, where relative stabilities of different coordination arrangements indicate that a mixture of Glu/Asp and His residues is favoured. A detailed comparison between different coordination shell geometries show that, in the aqueous phase, tetrahedral coordination is favoured in general. Our calculations show an interplay between dative covalent interactions and electrostatics which explains the observed trends. Multiple structures deposited in the Protein Data Bank support our findings, suggesting that the trends found in our work may be transferable to other Zn(II) metalloproteins with this type of coordination.

Mimosine is a nonprotein amino acid derived from plantsknown for its ability to bind to divalent and trivalent metal cations suchas Zn2+, Ni2+, Fe2+, orAl3+. This results in interesting antimicrobial andanticancer properties, which make mimosine a promising candidate fortherapeutic applications. One possibility is to incorporate mimosine intosynthetic short peptide drugs. However, how this amino acid affects thepeptide structure is not well understood, reducing our ability to designeffective therapeutic compounds. In this work, we used computersimulations to understand this question. Wefirst built parameters for themimosine residue to be used in combination with two classical forcefields of the Amber family. Then, we used atomistic molecular dynamicssimulations with the resulting parameter sets to evaluate the influence ofmimosine in the structural propensities for this amino acid. We comparedthe results of these simulations with homologous peptides, wheremimosine is replaced by either phenylalanine or tyrosine. We found that the strong dipole in mimosine induces a preference forconformations where the amino acid rings are stacked over more extended conformations. We validated our results using quantummechanical calculations, which provide a robust foundation for the outcome of our classical simulations

The amyloid-forming Aβpeptide is able to interact with metal cations to form very stable complexes that influence fibril formation and contribute to the onset of Alzheimer’s disease. Multiple structures of fragments of Aβwith different metals have been resolved experimentally to provide an atomic-level description of the metalprotein interactions. However, Aβis an intrinsically disordered protein (IDP), which is more amenable to an ensemble description. Molecular dynamics (MD) simulations can now reach the timescales needed to generate ensembles for this type of complexes. However, this requires accurate force fields both for the IDP and for the protein-metal interactions. Here we use state-of-the-art methods to generate force field parameters for the Zn(II) cations in a set of Aβcomplexes and combine them with the Amber99SB⋆ILDN optimized force field. We show that the new parameters provide an accurate description of the molecular ensembles for IDP-metal complexes. These ensembles are more heterogeneous than the NMR models deposited in the Protein Data Bank. We validate our results against experimental data and further optimize the ensembles using a Bayesian/Maximum entropy approach.

We have used near linear-scaling density functional theory (LS-DFT) methods including dispersion, for the first time, to study the interaction of two isomers, equatorial (Eq) and axial (Ax), of the [Mo(η3- C3H5)Br(CO)2(phen)] metal complex with the DNA G-quadruplexes (GQ) to gain insight on its cytoxicity. The LMKLL/DZDP level of calculation, which includes van der Waals contributions, with the SIESTA software was used to treat by means of first-principles computations the whole biological studied model system with 1000 atoms. Computed formation energies and the energy decomposition analysis (EDA) point to systems containing the Eq isomer as the most stable. However, when solvent effects are taken into account the systems containing the Ax isomer are the most stable. This Ax isomer was found interacting by means of end-stacking with the GQ and surprisingly totally inside the non-canonical secondary structure, where all the ligands of the metal complex produce several weak interactions with the DNA structure. On the other hand, the Eq isomer prefers to interact from outside by means of intercalation in which the ancillary ligands have also some role in the interaction. Nevertheless, some stable system was found for the Eq isomer in which the Br halogen atom was the main link through which the interaction is produced between the metal complex and DNA bases. For this case, the weak interactions produced by the ancillary ligands are very important, whereas no π − π stacking is found through the phen ligand. Such features and comparison with the results regarding the interaction of [Mo(η3-C3H5)Br(CO)2(phen)] metal complex with duplex DNA suggest that the [Mo(η3-C3H5)Br(CO)2(phen)] complex would have higher affinity and eventual selectivity for non-canonical DNA GQ structures.

The computational study of DNA and its interaction with ligands is a highly relevant area of research, with significant consequences for developing new therapeutic strategies. However, the computational description of such large and complex systems requires considering interactions of different types simultaneously in a balanced way, such as non-covalent weak interactions (namely hydrogen bonds and stacking), metal–ligand interactions, polarisation and charge transfer effects. All these considerations imply a real challenge for computational chemistry. The possibility of studying large biological systems using quantum methods for the entire system requires significant computational resources, with improvements in parallelisation and optimisation of theoretical strategies. Computational methods, such as Linear-Scaling Density Functional Theory (LS-DFT) and DLPNO-CCSD(T), may allow performing ab initio quantum mechanics calculations, including the electronic structure for large biological systems, in a reasonable computing time. In this work, we study the interaction of small molecules and cations with DNA (both duplex DNA and G-quadruplexes), comparing different computational methods: a LS-DFT method at the LMKLL/DZDP level of theory, semi-empirical methods (PM6-DH2 and PM7), mixed QM/MM, and DLPNO-CCSD(T). Our goal is to demonstrate the adequacy of LS-DFT to treat the different types of interactions present in DNA-dependent systems. We show that LMKLL/DZDP using SIESTA can yield very accurate geometries and energetics in all the different systems considered in this work: duplex DNA (dDNA), phenanthroline intercalating dDNA, G-quadruplexes, and metal-G-tetrads considering alkaline metals of different sizes. As far as we know, this is the first time that full G-quadruplex geometry optimisations have been carried out using a DFT method thanks to its linear-scaling capabilities. Moreover, we show that LS-DFT provides high-quality structures, and some semi-empirical Hamiltonians can also yield suitable geometries. However, DLPNO-CCSD(T) and LS-DFT are the only methods that accurately describe interaction energies for all the systems considered in our study., This research was financially supported by Diputación Foral de Gipuzkoa through the Gipuzkoa Fellows Program to A. G. This research was also financially supported by the Fundação para a Ciência e a Tecnologia (FCT) by means of Projects PTDC/QUI-QFI/29236/2017, UIDB/04046/2020, and UIDP/04046/2020 and by the Spanish Ministry of Economy, Industry and Competitiveness under the Maria de Maeztu Units of Excellence Program/MDM-2016-0618). A. G. is thankful to ARAID – Fundación Agencia Aragonesa para la Investigación y el Desarrollo for current funding in the frame of ARAID researchers. The authors also thank for technical and human support provided by IZO-SGI (SGIker) of UPV/EHU and European funding (ERDF and ESF). Financial support comes also from Eusko Jaurlaritza (Basque Government) through the project IT1254-19 and IT1584-22, from Spanish MICINN through Grant No. PID2019-107338RB-C61/AEI/10.13039/501100011033, and grant PGC2018-099321-B-100 from the Ministry of Science, Innovation and Universities through the Office of Science Research (MINECO/FEDER). Pseudopotentials and Numerical Atomic Orbitals Basis Dataset for SIESTA were provided by Simune Atomistics S. L. (www.simuneatomistics.com). S. E. thanks the Ministry of Higher Education and Scientific Research of Tunisia for the funding of intership carried out in Portugal and Spain. I. O. D. L. is also very grateful to CICnanoGUNE BRTA for his PhD grant.

Mimosine is a non-protein amino acid derived from plants known for its ability to bind to divalent or trivalent metal cations such as Zn$^{2+}$, Ni$^{2+}$, Fe$^{2+}$ or Al$^{3+}$. This results in interesting antimicrobial and anti-cancer properties, which make mimosine a promising candidate for therapeutic applications. One possibility is to incorporate mimosine into synthetic short peptide drugs. However, our understanding of how this amino acid affects peptide structure is still limited, reducing our ability to design effective therapeutic compounds. In this work, we used computer simulations to understand this question. We first build parameters for the mimosine residue to be used in combination with two classical force fields of the Amber family. Then, we used atomistic molecular dynamics simulations with the resulting parameter sets to evaluate the influence of mimosine in the structural propensities for this amino acid. We compared the results of these simulations with identical peptides where mimosine is replaced by either phenylalanine or tyrosine. We found that the strong dipole in mimosine induces a preference for conformations where the amino acid rings are stacked over more traditional conformations. We validated our results using quantum mechanical calculations, which provide a robust foundation to the outcome of our classical simulations.

The accumulation of microplastics (MPs) pollution at depths suggests the susceptibility of benthic organisms (e.g. seagrasses and their associated macro- and micro-organisms) to the effects of these pollutants. Little is known about the direct effects of MPs and their organic additives on marine bacteria, e.g. in one of the most ecologically significant groups, the diazotrophs or N2-fixing bacteria. To fill this gap of knowledge, we exposed marine diazotrophs found in association with the endemic Mediterranean seagrass Posidonia oceanica to pure MPs which differ in physical properties (e.g. density, hydrophobicity and/or size), namely, polyethylene (PE), polypropylene (PP), polyvinyl chloride (PVC) and polystyrene (PS) and to their most abundant associated organic additives (e.g. fluoranthene, 1,2,5,6,9,10-hexabromocyclododecane [HBCD] and dioctyl-phthalate [DEHP]). Growth, protein overexpression, direct physical interactions between MPs and bacteria, phosphorus (P) acquisition mechanisms and N2-fixation rates were evaluated. Our results show species-specific responses of the autotrophic and heterotrophic N2-fixing bacteria tested and the responses were dependent on the type and concentration of MPs and additives. N2-fixing cyanobacteria were positively affected by environmental and high concentrations of MPs (e.g. PVC), as opposed to heterotrophic strains, that were only positively affected with high concentrations of ∼120 µm-size MPs (detecting the overexpression of proteins related to plastic degradation and C-transport), and negatively affected by 1 µm-size PS beads. Generally, the organic additives (e.g. fluoranthene) had a deleterious effect in both autotrophic and heterotrophic N2-fixing bacteria and the magnitude of the effect is suggested to be dependent on bacterial size. We did not find evidences that specific N2-fixation rates were significantly affected by exposure to MPs, albeit changes in bacterial abundance can affect the bulk N2-fixation rates. In summary, we reported for the first time, the beneficial (the “good”), deleterious (the “bad”) and/or both (the “double-sword”) effects of exposure to MPs and their organic additives on diazotrophs found in association with seagrasses.

Little is known about the direct effects of microplastics (MPs) and their organic additives on marine bacteria, considering their role in the nutrient cycles, e.g., N-cycles through the N2-fixation, or in the microbial food web. To fill this gap of knowledge, we exposed marine bacteria, specifically diazotrophs, to pure MPs which differ in physical properties (e.g., density, hydrophobicity, and/or size), namely, polyethylene, polypropylene, polyvinyl chloride and polystyrene, and to their most abundant associated organic additives (e.g., fluoranthene, 1,2,5,6,9,10-hexabromocyclododecane and dioctyl-phthalate). Growth, protein overproduction, direct physical interactions between MPs and bacteria, phosphorus acquisition mechanisms and/or N2-fixation rates were evaluated. Cyanobacteria were positively affected by environmental and high concentrations of MPs, as opposed to heterotrophic strains, that were only positively affected with high concentrations of ~120 μm-size MPs (detecting the overproduction of proteins related to plastic degradation and C-transport), and negatively affected by 1 μm-size PS beads. Generally, the organic additives had a deleterious effect in both autotrophic and heterotrophic bacteria and the magnitude of the effect is suggested to be dependent on bacterial size. Our results show species-specific responses of the autotrophic and heterotrophic bacteria tested and the responses (beneficial: the “good,” deleterious: the “bad” and/or both: the “double-sword”) were dependent on the type and concentration of MPs and additives. This suggests the need to determine the threshold levels of MPs and additives concentrations starting from which significant effects can be observed for key microbial populations in marine systems, and these data are necessary for effective environmental quality control management.

Pregnancy strongly influences the thyroid gland and its function. Thyroid guidelines recommend a 30 to 50% increase of the preconceptional levothyroxine dose in women with hypothyroidism, when pregnancy is diagnosed.A 33 year-old, 8-week pregnant woman with hypothyroidism, presents with a 2-week history of palpitations, sweating, nervousness and fatigue. Physical examination shows tachycardia (108 bpm), distal tremors and diffuse goiter. After biochemical confirmation of hyperthyroidism, her levothyroxine dose is reduced and finally interrupted. Propylthiouracil is started and maintained until after the delivery of a healthy baby at week 40. Two weeks postpartum, hyperthyroidism worsens and propylthiouracil is replaced by methimazole. Eighteen months after delivery 7.5 mCi 131Iodine was given. Two months later, hypothyroidism developed and levothyroxine was initiated.Although conversion of Hashimoto's hypothyroidism into Graves' disease is exceptional in pregnancy, pregnant women with autoimmune hypothyroidism should ideally have their TSH concentrations measured before empirically increasing their levothyroxine dose.