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The chemical behaviour of molecules can be significantly modified by confinement to volumes comparable to the dimensions of the molecules. Although such confined spaces can be found in various nanostructured materials, such as zeolites, nanoporous organic frameworks and colloidal nanocrystal assemblies, the slow diffusion of molecules in and out of these materials has greatly hampered studying the effect of confinement on their physicochemical properties. Here, we show that this diffusion limitation can be overcome by reversibly creating and destroying confined environments by means of ultraviolet and visible light irradiation. We use colloidal nanocrystals functionalized with light-responsive ligands that readily self-assemble and trap various molecules from the surrounding bulk solution. Once trapped, these molecules can undergo chemical reactions with increased rates and with stereoselectivities significantly different from those in bulk solution. Illumination with visible light disassembles these nanoflasks, releasing the product in solution and thereby establishes a catalytic cycle. These dynamic nanoflasks can be useful for studying chemical reactivities in confined environments and for synthesizing molecules that are otherwise hard to achieve in bulk solution. Colloidal nanocrystals functionalized with light-responsive ligands can be cyclically assembled and disassembled to create nanoscale environments where chemical reaction rates are enhanced and stereoselectivities can be controlled.

The defining feature of Parkinson disease (PD) and Lewy body dementia (LBD) is the accumulation of alpha-synuclein (Asyn) fibrils in Lewy bodies and Lewy neurites. Here we develop and validate a method to amplify Asyn fibrils extracted from LBD postmortem tissue samples and use solid state nuclear magnetic resonance (SSNMR) studies to determine atomic resolution structure. Amplified LBD Asyn fibrils comprise a mixture of single protofilament and two protofilament fibrils with very low twist. The protofilament fold is highly similar to the fold determined by a recent cryo-electron microscopy study for a minority population of twisted single protofilament fibrils extracted from LBD tissue. These results expand the structural characterization of LBD Asyn fibrils and approaches for studying disease mechanisms, imaging agents and therapeutics targeting Asyn. The accumulation of alpha-synuclein fibrils within neurons is the defining feature of Lewy body dementia (LBD). Here the authors report a method to produce large quantities of alpha-synuclein fibrils that reproduce the complex structure of the fibrils that accumulate in LBD brain tissue.

The nucleation and growth of solids from solutions impacts many natural processes and is fundamental to applications in materials engineering and medicine. For a crystalline solid, the nucleus is a nanoscale cluster of ordered atoms that forms through mechanisms still poorly understood. In particular, it is unclear whether a nucleus forms spontaneously from solution via a single- or multiple-step process. Here, using in situ electron microscopy, we show how gold and silver nanocrystals nucleate from supersaturated aqueous solutions in three distinct steps: spinodal decomposition into solute-rich and solute-poor liquid phases, nucleation of amorphous nanoclusters within the metal-rich liquid phase, followed by crystallization of these amorphous clusters. Our ab initio calculations on gold nucleation suggest that these steps might be associated with strong gold–gold atom coupling and water-mediated metastable gold complexes. The understanding of intermediate steps in nuclei formation has important implications for the formation and growth of both crystalline and amorphous materials. Crystals grow from nuclei. In systems where nuclei are nanometre-sized and form quickly, it is difficult to determine the mechanism of their formation. Now, through in situ TEM, the demixing of a supersaturated aqueous gold solution into metastable gold-poor and gold-rich liquid phases is observed, the latter yielding stable clusters that become nuclei for nanocrystal growth.

Viral infections kill millions yearly. Available antiviral drugs are virus-specific and active against a limited panel of human pathogens. There are broad-spectrum substances that prevent the first step of virus-cell interaction by mimicking heparan sulfate proteoglycans (HSPG), the highly conserved target of viral attachment ligands (VALs). The reversible binding mechanism prevents their use as a drug, because, upon dilution, the inhibition is lost. Known VALs are made of closely packed repeating units, but the aforementioned substances are able to bind only a few of them. We designed antiviral nanoparticles with long and flexible linkers mimicking HSPG, allowing for effective viral association with a binding that we simulate to be strong and multivalent to the VAL repeating units, generating forces (∼190 pN) that eventually lead to irreversible viral deformation. Virucidal assays, electron microscopy images, and molecular dynamics simulations support the proposed mechanism. These particles show no cytotoxicity, and in vitro nanomolar irreversible activity against herpes simplex virus (HSV), human papilloma virus, respiratory syncytial virus (RSV), dengue and lenti virus. They are active ex vivo in human cervicovaginal histocultures infected by HSV-2 and in vivo in mice infected with RSV.

Blocking the formation, growth, and breaking of amyloid fibrils by synthetic nanosystems could provide a treatment of neurodegenerative diseases. With this in mind, here atomistic molecular dynamics simulations are used to screen for nanoparticles (NPs), covered with different mixtures of ligands, including positively and negatively charged ligands, Aβ 40-cut-peptide, and synthetic inhibitor ligands, in their selective coupling to Aβ 40 peptides and their fibrils. The simulations reveal that only Aβ 40-cut-peptide-covered NPs have strong and selective coupling to Aβ 40 monomers. On the other hand, positive, positive-neutral, Janus, and peptide NPs couple to the beta sheet surfaces of Aβ 40 fibrils and only the negative-neutral NPs couple to the fibril tips.

In this thesis, we use quantum and classical methods to precisely model nanoscale materials on their own and in contact with biological components (nanomedicines). Most of the studies have been performed in close collaborations with experimentalists. First, we perform multiscale modeling of materials, using quantum ab initio methods and classical atomistic molecular dynamics (MD) simulations. We study (1) the nucleation of gold nanocrystals from its aqueous solution (Au(Cl4)-), (2) the dynamics of reaction intermediates (Si(OH)4) during wet etching of silicon nanopillars, (3) a capacitive gas sensing at the interface of an ionic liquid and a gold electrode, and (4) a reversible self-assembly of azobenzene-functionalized gold nanoparticles (NPs) in toluene. Second, we use atomistic MD simulations to model the interactions of nanoscale systems (NPs, micelles) with proteins and lipid bilayers. We investigate (5) irreversible interactions of functionalized NPs with selected viruses (HPV, dengue virus), (6) interactions of predesigned NPs with an Aβ40 amyloid fibril, (7) the enhancement of an enzymatic activity on the surfaces of ligated quantum dots, (8) the effect of PEG chain length in dendron micelles (DM) on the charge-dependent DM-cellular interactions, and (9) the effect of structural properties of DMs on their target-mediated cellular interactions.

ABSTRACT Purpose An oligonucleotide termed ‘T-oligo’ having sequence homology with telomere overhang has shown cytotoxicity in multiple cancers. We have demonstrated that T-oligo can induce apoptosis in androgen independent prostate cancer cell line DU-145. In this report, we evaluate the use of star-shaped tetraspermine (SSTS) for delivery of T-oligo. Methods SSTS was synthesized from spermine and its intrinsic cytotoxicity towards DU-145 cells was compared with spermine and branched polyethyleneimine (bPEI). Atomistic molecular dynamic (MD) simulations were conducted to understand binding and complexation of spermine and SSTS with T-oligo. Complexation was also determined using gel electrophoresis and SYBR gold assay. Complexes were characterized for size, cellular uptake and antiproliferative effect. Results SSTS exhibited significantly lower toxicity than spermine and bPEI. Its affinity towards T-oligo was significantly higher than spermine as determined by experimental studies and confirmed by MD simulations and it formed stable complexes (TONPs) with T-oligo. TONPs facilitated cellular uptake and nuclear accumulation of T-oligo and their cytotoxic potential was observed at concentration several folds lower than that required for T-oligo alone. Conclusion SSTS significantly enhanced therapeutic benefits associated with the use of T-oligo and can be developed as a delivery vehicle for its in - vivo therapeutic applications.

The defining feature of Parkinson disease (PD) and Lewy body dementia (LBD) is the accumulation of alpha-synuclein (Asyn) fibrils in Lewy bodies and Lewy neurites. We developed and validated a novel method to amplify Asyn fibrils extracted from LBD postmortem tissue samples and used solid state nuclear magnetic resonance (SSNMR) studies to determine atomic resolution structure. LBD Asyn fibrils comprise two protofilaments with pseudo-21 helical screw symmetry, very low twist and an interface formed by antiparallel beta strands of residues 85-93. The fold is highly similar to the fold determined by a recent cryo-electron microscopy study for a minority population of twisted single protofilament fibrils extracted from LBD tissue. These results expand the structural landscape of LBD Asyn fibrils and inform further studies of disease mechanisms, imaging agents and therapeutics targeting Asyn.Competing Interest StatementAuthors Kotzbauer, Dhavale and O'Shea have a patent application pending titled \"Tissue-Seeded Fibrils and Methods of Making and Using Same\". Other authors have declared no competing interest.

Nucleation and growth of solids from solutions impacts many natural processes and are fundamental to applications in materials engineering and medicine. For a crystalline solid, the nucleus is a nanoscale cluster of ordered atoms, which forms through mechanisms that are still poorly understood. These mechanisms have important consequences on the morphology and nucleation rates of the resultant crystals but it is unclear whether a nucleus forms spontaneously from solution in a single step or through multiple steps. Using in-situ electron microscopy, we observe and quantify how gold and silver nanocrystals nucleate from a supersaturated aqueous gold and silver solution in three distinct steps: (I) spinodal decomposition into solute-rich and solute-poor liquid phases, (II) nucleation of amorphous gold nanoclusters within the gold-rich liquid phase, followed by (III) crystallization of these amorphous clusters. Our ab-initio calculations on gold nucleation suggest that these steps might be associated with strong gold-gold atom coupling and water-mediated metastable gold complexes. The understanding of intermediate steps in nuclei formation has important implications for the formation and growth of both crystalline and amorphous materials.