Computational Investigation of the Binding Dynamics of Oligo -Phenylene Ethynylene Fluorescence Sensors and Aβ Oligomers.

Amyloid protein aggregates are pathological hallmarks of neurodegenerative disorders such as Alzheimer's (AD) and Parkinson's (PD) diseases and are believed to be formed well before the onset of neurodegeneration and cognitive impairment. Monitoring the course of protein aggregation is thus vital to understanding and combating these diseases. We have recently demonstrated that a novel class of fluorescence sensors, oligomeric -phenylene ethynylene (PE)-based electrolytes (OPEs) selectively bind to and detect prefibrillar and fibrillar aggregates of AD-related amyloid-β (Aβ) peptides over monomeric Aβ.

Computational Study of the Driving Forces and Dynamics of Curcumin Binding to Amyloid-β Protofibrils.

Oligomeric aggregates of the amyloid-β (Aβ) peptide are believed to be the primary toxic species that initiate events leading to neurodegeneration and cognitive decline in Alzheimer's disease (AD). Small molecules that interfere with Aβ aggregation and/or neurotoxicity are being investigated as potential therapeutics for AD, including naturally occurring polyphenols. We have recently shown that curcumin exerts a neuroprotective effect against Aβ40-induced toxicity on cultured neuronal cells through two possible concerted pathways, ameliorating Aβ oligomer-induced toxicity and inducing the formation of nontoxic Aβ oligomers, both of which involve curcumin binding to Aβ oligomers.

Oligomeric Conjugated Polyelectrolytes Display Site-Preferential Binding to an MS2 Viral Capsid.

Opportunistic bacteria and viruses are a worldwide health threat prompting the need to develop new targeting modalities. A class of novel synthetic poly(phenylene ethynylene) (PPE)-based oligomeric conjugated polyelectrolytes (OPEs) have demonstrated potent wide-spectrum biocidal activity. A subset of cationic OPEs display high antiviral activity against the MS2 bacteriophage.

Diblock copolymer micelles and supported films with noncovalently incorporated chromophores: a modular platform for efficient energy transfer.

We report generation of modular, artificial light-harvesting assemblies where an amphiphilic diblock copolymer, poly(ethylene oxide)-block-poly(butadiene), serves as the framework for noncovalent organization of BODIPY-based energy donor and bacteriochlorin-based energy acceptor chromophores. The assemblies are adaptive and form well-defined micelles in aqueous solution and high-quality monolayer and bilayer films on solid supports, with the latter showing greater than 90% energy transfer efficiency. This study lays the groundwork for further development of modular, polymer-based materials for light harvesting and other photonic applications.

Enzyme-specific sensors via aggregation of charged p-phenylene ethynylenes.

Chemical and biological sensors are sought for their ability to detect enzymes as biomarkers for symptoms of various disorders, or the presence of chemical pollutants or poisons. p-Phenylene ethynylene oligomers with pendant charged groups have been recently shown to have ideal photophysical properties for sensing. In this study, one anionic and one cationic oligomer are combined with substrates that are susceptible to enzymatic degradation by phospholipases or acetylcholinesterases.

Computational study of bacterial membrane disruption by cationic biocides: structural basis for water pore formation.

The development of biocides as disinfectants that do not induce bacterial resistance is crucial to health care since hospital-acquired infections afflict millions of patients every year. Recent experimental studies of a class of cationic biocides based on the phenylene ethynylene backbone, known as OPEs, have revealed that their biocidal activity is accompanied by strong morphology changes to bacterial cell membranes. In vitro studies of bacterial membrane mimics have shown changes to the lipid phase that are dependent on the length and orientation of the cationic moieties on the backbone.

Calculation of iron transport through human H-chain ferritin.

Influx of ferrous ions from the cytoplasm through 3-fold pores in the shell of ferritin protein is computed using a 3-dimensional Poisson-Nernst-Planck electrodiffusion model, with inputs such as the pore structure and the diffusivity profile of permeant Fe(2+) ions extracted from all-atom molecular dynamics (MD) simulations. These calculations successfully reproduce experimental estimates of the transit time of Fe(2+) through the ferritin coat, which is on the millisecond time scale and hence much too long to be directly simulated via all-atom MD. This is also much longer than the typical time scale for ion transit in standard membrane spanning ion channels whose pores bear structural similarity to that of the 3-fold ferritin pore.

Structural basis for aggregation mode of oligo-p-phenylene ethynylenes with ionic surfactants.

In this letter, the aggregation modes of two classes of ionic p-phenylene ethynylene oligomers with oppositely charged surfactants are studied. The location of the ionic side chains was found to influence the type of aggregate formed when an equivalent number of surfactant molecules are added to solution. When the charged groups were located at the terminal ends of the molecule, strong H-aggregates were observed to form.

Cationic oligo-p-phenylene ethynylenes form complexes with surfactants for long-term light-activated biocidal applications.

Cationic oligo-p-phenylene ethynylenes are highly effective light-activated biocides that deal broad-spectrum damage to a variety of pathogens, including bacteria. A potential problem arising in the long-term usage of these compounds is photochemical breakdown, which nullifies their biocidal activity. Recent work has shown that these molecules complex with oppositely-charged surfactants, and that the resulting complexes are protected from photodegradation.

Photochemistry of "end-only" oligo-p-phenylene ethynylenes: complexation with sodium dodecyl sulfate reduces solvent accessibility.

Cationic oligo-p-phenylene ethynylenes are very effective light-activated biocides and biosensors but degrade upon exposure to light. In this study, we explore the photochemistry of a class of "end-only" compounds from this series, which have cationic moieties on the ends of the backbone. Product characterization by mass spectrometry reveals that the photoreactivity of these molecules is higher than that of a previously studied oligomer and that the primary products of photolysis result from the addition of water or oxygen across the triple bond.

Metal binding sites of human H-chain ferritin and iron transport mechanism to the ferroxidase sites: a molecular dynamics simulation study.

We study via all atom classical molecular dynamics (MD) simulation the process of uptake of ferrous ions (Fe(2+)) into the human ferritin protein and the catalytic ferroxidase sites via pores ("channels") in the interior of the protein. We observe that the three-fold hydrophilic channels serve as the main entrance pathway for the Fe(2+) ions. The binding sites along the ion pathway are investigated.

Molecular dynamics simulation study of the interaction of cationic biocides with lipid bilayers: aggregation effects and bilayer damage.

A novel class of phenylene ethynylene polyelectrolyte oligomers (OPEs) has been found to be effective biocidal agents against a variety of pathogens. The mechanism of attack is not yet fully understood. Recent studies have shown that OPEs cause catastrophic damage to large unilamellar vesicles.

A molecular dynamics and computational study of ligand docking and electron transfer in ferritins.

The mechanism of the reductive release of iron from the cavity of the iron storage protein, ferritin, has been difficult to confirm on the molecular level using experimental studies. In this paper, we use a variety of computational tools to study the binding of flavin redox agents to the protein surface, and the subsequent electron transfer (ET) through the protein coat. Flavin binding sites are identified that represent efficient routes to reduction of Fe(III) across the protein coat in human and bacterial ferritins.

Photochemistry of a Model Cationic p-Phenylene Ethynylene in Water.

One important aspect of p-phenylene-ethynylenes that has not yet been explored is the possible photochemical reactions that can take place in different chemical environments. This is especially important when considering the possible breakdown of these compounds in applications that involve exposure to light, air, and water. In this Letter, a study of the photochemical reaction processes of a cationic oligomer based on the p-phenylene-ethynylene repeat unit is performed in aqueous solution in both the presence and absence of oxygen.

The targeted delivery of multicomponent cargos to cancer cells by nanoporous particle-supported lipid bilayers.

Encapsulation of drugs within nanocarriers that selectively target malignant cells promises to mitigate side effects of conventional chemotherapy and to enable delivery of the unique drug combinations needed for personalized medicine. To realize this potential, however, targeted nanocarriers must simultaneously overcome multiple challenges, including specificity, stability and a high capacity for disparate cargos. Here we report porous nanoparticle-supported lipid bilayers (protocells) that synergistically combine properties of liposomes and nanoporous particles.

Synthesis, self-assembly, and photophysical properties of cationic oligo(p-phenyleneethynylene)s.

Three series of cationic oligo p-phenyleneethynylenes (OPEs) have been synthesized to study their structure-property relationships and gain insights into the transition from molecular to macromolecular properties. The absorbance maxima and molar extinction coefficients in all three sets increase with increasing number of repeat units; however, the increase in λ(max) between the oligomers having 2 and 3 repeat units is very small, and the oligomer having 3 repeat units shows virtually the same spectra as a p-phenyleneethynylene polymer having 49 repeat units. A computational study of the oligomers using density functional theory calculations indicates that while the simplest oligomers (OPE-1) are fully conjugated, the larger oligomers are nonplanar and the limiting "segment chromophore" may be confined to a near-planar segment extending over three or four phenyl rings.

Effectiveness of perturbation theory approaches for computing non-condon electron transfer dynamics in condensed phases.

A description of electron transfer in condensed-phase media requires models that adequately describe the coupling of the electronic degrees of freedom to the surrounding nuclear coordinates. The spin-boson model has been the canonical model used to understand quantum dynamic processes in condensed-phase media over the last 25 years. Inherent in the standard model of a two-state quantum system coupled to a bosonic bath is the assumption that the Condon approximation is valid.

Condensed-phase relaxation of multilevel quantum systems. II. Comparison of path integral calculations and second-order relaxation theory for a nondegenerate three-level system.

An exactly solvable model of multisite condensed-phase vibrational relaxation was studied in Paper I (Peter, S.; Evans, D. G.

Condensed-phase relaxation of multilevel quantum systems. I. An exactly solvable model.

An analytically solvable model of multilevel condensed-phase quantum dynamics relevant to vibrational relaxation and electron transfer is presented. Exact solutions are derived for the reduced system density matrix dynamics of a degenerate N-level quantum system characterized by nearest-neighbor hopping and off-diagonal coupling (which is linear in the bath coordinates) to a harmonic oscillator bath. We demonstrate that for N> 2 the long-time steady-state system site occupation probabilities are not the same for all sites; that is, they are distributed in a non-Boltzmann manner, which depends on the initial conditions and the number of levels in the system.