Multiscale Modeling of Nanoparticles Growth, Self-assembly and Applications in Nanomedicine

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

Template-Free Hierarchical Self-Assembly of Iron Diselenide Nanoparticles into Mesoscale Hedgehogs

The ability of semiconductor nanoparticles (NPs) to self-assemble has been known for several decades. However, the limits of the geometrical and functional complexity for the self-assembled nanostructures made from simple often polydispersed NPs are still continuing to amaze researchers. We report here the self-assembly of primary ∼2–4 nm FeSe₂ NPs with puck-like shapes into either (a) monocrystalline nanosheets ∼5.5 nm thick and ∼1000 nm in lateral dimensions or (b) mesoscale hedgehogs ∼550 nm in diameter with spikes of ∼250 nm in length, and ∼10–15 nm in diameter, the path of the assembly is determined by the concentration of dodecanethiol (DT) in the reaction media. The nanosheets represent the constitutive part of hedgehogs. They are rolled into scrolls and assembled around a single core with distinct radial orientation forming nanoscale “needles” approximately doubling its fractal dimension of these objects. The core is assembled from primary NPs and nanoribbons. The size distribution of the mesoscale hedgehogs can be as low as 3.8%, indicating a self-limited mechanism of the assembly. Molecular dynamics simulation indicates that the primary FeSe₂ particles have mobile edge atoms and asymmetric basal surfaces. The top-bottom asymmetry of the puck-like NPs originates from the Fe-rich/Se-rich stripes on the (011) surface of the orthorhombic FeSe₂ crystal lattice, displaying 2.7 nm periodicity that is comparable to the lateral size of the primary NPs. As the concentration of DT increases, the NPs bind to additional metal sites, which increases the chemical and topographic asymmetry and switches the assembly pathways from nanosheets to hedgehogs. These results demonstrate that the self-assembly of NPs with non-biological surface ligands and without any biological templates results in morphogenesis of inorganic superstructures with complexity comparable to that of biological assemblies, for instance mimivirus. The semiconductor nature of FeSe₂ hedgehogs enables their utilizations in catalysis, drug delivery, optics, and energy storage

Transient Clustering of Reaction Intermediates during Wet Etching of Silicon Nanostructures

Wet chemical etching is a key process in fabricating silicon (Si) nanostructures. Currently, wet etching of Si is proposed to occur through the reaction of surface Si atoms with etchant molecules, forming etch intermediates that dissolve directly into the bulk etchant solution. Here, using in situ transmission electron microscopy (TEM), we follow the nanoscale wet etch dynamics of amorphous Si (a-Si) nanopillars in real-time and show that intermediates generated during alkaline wet etching first aggregate as nanoclusters on the Si surface and then detach from the surface before dissolving in the etchant solution. Molecular dynamics simulations reveal that the molecules of etch intermediates remain weakly bound to the hydroxylated Si surface during the etching and aggregate into nanoclusters via surface diffusion instead of directly diffusing into the etchant solution. We confirmed this model experimentally by suppressing the formation of nanoclusters of etch intermediates on the Si surfaces by shielding the hydroxylated Si sites with large ions. These results suggest that the interaction of etch intermediates with etching surfaces controls the solubility of reaction intermediates and is an important parameter in fabricating densely packed clean 3D nanostructures for future generation microelectronics

Poly(ethylene glycol) Corona Chain Length Controls End-Group-Dependent Cell Interactions of Dendron Micelles

To systematically investigate the relationship among surface charge, PEG chain length, and nano–bio interactions of dendron-based micelles (DMs), a series of PEGylated DMs with various end groups (−NH₂, −Ac, and −COOH) and PEG chain lengths (600 and 2000 g/mol) are prepared and tested <i>in vitro</i>. The DMs with longer PEG chains (DM_2K) do not interact with cells despite their positively charged surfaces. In sharp contrast, the DMs with shorter PEG chains (DM₆₀₀) exhibit charge-dependent cellular interactions, as observed in both <i>in vitro</i> and molecular dynamics (MD) simulation results. Furthermore, all DMs with different charges display enhanced stability for hydrophobic dye encapsulation compared to conventional linear-block copolymer-based micelles, by allowing only a minimal leakage of the dye <i>in vitro</i>. Our results demonstrate the critical roles of the PEG chain length and polymeric architecture on the terminal charge effect and the stability of micelles, which provides an important design cue for polymeric micelles

Tuning the Selectivity of Dendron Micelles Through Variations of the Poly(ethylene glycol) Corona

Engineering controllable cellular interactions into nanoscale drug delivery systems is key to enable their full potential. Here, using folic acid (FA) as a model targeting ligand and dendron micelles (DM) as a nanoparticle (NP) platform, we present a comprehensive experimental and modeling investigation of the structural properties of DMs that govern the formation of controllable, FA-mediated cellular interactions. Our experimental results demonstrate that a high level of control over the specific cell interactions of FA-targeted DMs can be achieved through modulation of the PEG corona length and the FA content. Using various molecular weight PEGs (0<i>.</i>6K, 1K, and 2K g/mol) and contents of dendron-FA conjugate incorporated into DMs (0, 5, 10, 25 wt %), the cell interactions of the targeted DMs could be controlled to exhibit minimal to >25-fold enhancement over nontargeted DMs. Molecular dynamics simulations indicated that structural characteristics, such as solvent accessible surface area of FA, local PEG density near FA, and FA mobility, account in part for the experimental differences in cellular interactions. The molecular structure that allows FA to depart from the surface of DMs to facilitate the initial cell surface binding was revealed to be the most important contributor for determining FA-mediated cellular interactions of DMs. The modular properties of DMs in controlling their specific cell interactions support the potential of DMs as a delivery platform and offer design cues for future development of targeted NPs

Highly Sensitive Capacitive Gas Sensing at Ionic Liquid–Electrode Interfaces

We have developed an ultrasensitive gas-detection method based on the measurement of a differential capacitance of electrified ionic liquid (IL) electrode interfaces in the presence and absence of adsorbed gas molecules. The observed change of differential capacitance has a local maximum at a certain potential that is unique for each type of gas, and its amplitude is related to the concentration of the gas molecules. We establish and validate this gas-sensing method by characterizing SO₂ detection at ppb levels with less than 1.8% signal from other interfering species (i.e., CO₂, O₂, NO₂, NO, SO₂, H₂O, H₂, and cyclohexane, tested at the same concentration as SO₂). This study opens a new avenue of utilizing tunable electrified IL–electrode interfaces for selective sensing of molecules with a kinetic size resolution of 0.1 Å

Confined, Oriented, and Electrically Anisotropic Graphene Wrinkles on Bacteria

Curvature-induced dipole moment and orbital rehybridization in graphene wrinkles modify its electrical properties and induces transport anisotropy. Current wrinkling processes are based on contraction of the entire substrate and do not produce confined or directed wrinkles. Here we show that selective desiccation of a bacterium under impermeable and flexible graphene <i>via</i> a flap-valve operation produces axially aligned graphene wrinkles of wavelength 32.4–34.3 nm, consistent with modified Föppl–von Kármán mechanics (confinement ∼0.7 × 4 μm²). Further, an electrophoretically oriented bacterial device with confined wrinkles aligned with van der Pauw electrodes was fabricated and exhibited an anisotropic transport barrier (Δ<i>E</i> = 1.69 meV). Theoretical models were developed to describe the wrinkle formation mechanism. The results obtained show bio-induced production of confined, well-oriented, and electrically anisotropic graphene wrinkles, which can be applied in electronics, bioelectromechanics, and strain patterning

Elucidating Surface Ligand-Dependent Kinetic Enhancement of Proteolytic Activity at Surface-Modified Quantum Dots

Combining biomolecules such as enzymes with nanoparticles has much to offer for creating next generation synergistically functional bionanomaterials. However, almost nothing is known about how these two disparate components interact at this critical biomolecular-materials interface to give rise to improved activity and emergent properties. Here we examine how the nanoparticle surface can influence and increase localized enzyme activity using a designer experimental system consisting of trypsin proteolysis acting on peptide-substrates displayed around semiconductor quantum dots (QDs). To minimize the complexity of analyzing this system, only the chemical nature of the QD surface functionalizing ligands were modified. This was accomplished by synthesizing a series of QD ligands that were either positively or negatively charged, zwitterionic, neutral, and with differing lengths. The QDs were then assembled with different ratios of dye-labeled peptide substrates and exposed to trypsin giving rise to progress curves that were monitored by Förster resonance energy transfer (FRET). The resulting trypsin activity profiles were analyzed in the context of detailed molecular dynamics simulations of key interactions occurring at this interface. Overall, we find that a combination of factors can give rise to a localized activity that was 35-fold higher than comparable freely diffusing enzyme–substrate interactions. Contributing factors include the peptide substrate being prominently displayed extending from the QD surface and not sterically hindered by the longer surface ligands in conjunction with the presence of electrostatic and other productive attractive forces between the enzyme and the QD surface. An intimate understanding of such critical interactions at this interface can produce a set of guidelines that will allow the rational design of next generation high-activity bionanocomposites and theranostics