72 research outputs found
Preface to Special Topic: Amyloid Aggregation: Characterization, Function and Molecular Mechanisms
Polymorphism in Alzheimer AĪ² Amyloid Organization Reflects Conformational Selection in a Rugged Energy Landscape
Structure of Large NitrateāWater Clusters at Ambient Temperatures: Simulations with Effective Fragment Potentials and Force Fields with Implications for Atmospheric Chemistry
Structural properties of large NO3āĀ·(H2O)n (n = 15ā500) clusters are studied by Monte Carlo simulations using effective fragment potentials (EFPs) and by classical molecular dynamics simulations using a polarizable empirical force field. The simulation results are analyzed with a focus on the description of hydrogen bonding and solvation in the clusters. In addition, a comparison between the electronic structure based EFP and the classical force field description of the 32 water cluster system is presented. The EFP simulations, which focused on the cases of n = 15 and 32, show an internal, fully solvated structure and a āsurface adsorbedā structure for the 32 water cluster at 300 K, with the latter configuration being more probable. The internal solvated structure and the āsurface adsorbedā structure differ considerably in their hydrogen bonding coordination numbers. The force field based simulations agree qualitatively with these results, and the local geometry of NO3ā and solvation at the surface-adsorbed site in the force field simulations are similar to those predicted using EFPs. Differences and similarities between the description of hydrogen bonding of the anion in the two approaches are discussed. Extensive classical force field based simulations at 250 K predict that long time scale stability of āinternalā NO3ā, which is characteristic of extended bulk aqueous interfaces, emerges only for n \u3e 300. Ab initio MĆøllerāPlesset perturbation theory is used to test the geometries of selected surface and interior anions for n = 32, and the results are compared to the EFP and MD simulations. Qualitatively, all approaches agree that surface structures are preferred over the interior structures for clusters of this size. The relatively large aqueous clusters of NO3ā studied here are of comparable size to clusters that lead to new particle formation in air. Nitrate ions on the surface of such clusters may have significantly different photochemistry than the internal species. The possible implications of surface-adsorbed nitrate ions for atmospheric chemistry are discussed
the unusual metal ion binding ability of histidyl tags and their mutated derivatives
Peptides that consist of repeated sequences of alternating histidines and alanines strongly bind Cu(ii) and form Ī±-helical structures
Cation Diffusion Facilitators Transport Initiation and Regulation Is Mediated by Cation Induced Conformational Changes of the Cytoplasmic Domain
Cation diffusion facilitators (CDF) are part of a highly conserved protein family that maintains cellular divalent cation homeostasis in all domains of life. CDF's were shown to be involved in several human diseases, such as Type-II diabetes and neurodegenerative diseases. In this work, we employed a multi-disciplinary approach to study the activation mechanism of the CDF protein family. For this we used MamM, one of the main ion transporters of magnetosomes - bacterial organelles that enable magnetotactic bacteria to orientate along geomagnetic fields. Our results reveal that the cytosolic domain of MamM forms a stable dimer that undergoes distinct conformational changes upon divalent cation binding. MamM conformational change is associated with three metal binding sites that were identified and characterized. Altogether, our results provide a novel auto-regulation mode of action model in which the cytosolic domain's conformational changes upon ligand binding allows the priming of the CDF into its transport mode
Synergistic Interactions between Repeats in Tau Protein and AĪ² Amyloids May Be Responsible for Accelerated Aggregation via Polymorphic States
Ionization of N2O4 in contact with water: mechanism, time scales and atmospheric implications.
Interactions between AĪ² and mutated Tau lead to polymorphism and induce aggregation of AĪ²-mutated tau oligomeric complexes.
One of the main hallmarks of the fronto-temporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17) is the accumulation of neurofibrillary tangles in the brain as an outcome of the aggregation of mutated tau protein. This process occurs due to a number of genetic mutations in the MAPT gene. One of these mutations is the āK280 mutation in the tau R2 repeat domain, which promotes the aggregation vis-Ć -vis that for the wild-type tau. Experimental studies have shown that in Alzheimer's disease AĪ² peptide forms aggregates both with itself and with wild-type tau. By analogy, in FTDP-17, it is likely that there are interactions between AĪ² and mutated tau, but the molecular mechanisms underlying such interactions remain to be elucidated. Thus, to investigate the interactions between AĪ² and mutated tau, we constructed fourteen āK280 mutated tau-AĪ²17-42 oligomeric complexes. In seven of the mutated tau-AĪ²17-42 oligoemric complexes the mutated tau oligomers exhibited hydrophobic interactions in their core domain, and in the other seven mutated tau-AĪ²17-42 oligoemric complexes the mutated tau oligomers exhibited salt-bridge interactions in their core domain. We considered two types of interactions between mutated tau oligomers and AĪ² oligomers: interactions of one monomer of the AĪ² oligomer with one monomer of the mutated tau oligomer to form a single-layer conformation, and interactions of the entire AĪ² oligomer with the entire mutated tau oligomer to form a double-layer conformation. We also considered parallel arrangements of AĪ² trimers alternating with mutated tau trimers in a single-layer conformation. Our results demonstrate that in the interactions of AĪ² and mutated tau oligomers, polymorphic mutated tau-AĪ²17-42 oligomeric complexes were observed, with a slight preference for the double-layer conformation. AĪ² trimers alternating with mutated tau trimers constituted a structurally stable confined Ī²-structure, albeit one that was energetically less stable than all the other constructed models
Study of Molecular Mechanisms of Ī±āSynuclein Assembly: Insight into a CrossāĪ² Structure in the NāTermini of New Ī±āSynuclein Fibrils
Investigating the Interactions between AĪ² and Amylin: Insight into the Link between Alzheimer's and Type II Diabetes
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