The Redinbo Laboratory uses the tools of structural, molecular and chemical biology to examine a range of dynamic cellular processes central to human health. Current projects include the discovery of new antimicrobials targeted to drug-resistant bacteria, the design of novel proteins engineered to detect and eliminate toxic chemicals, and the development of small-molecule to cell-based methods to improve anticancer chemotherapeutics. In addition, we continue to focus on determining the crystal structures of macromolecular complexes, including those involving human nuclear receptors central to transcriptional regulation, bacterial proteins involved in DNA manipulation and human cell contact, and enzymes central to key cellular processes.
The Lockett Group uses a multidisciplinary approach, combining aspects of analytical chemistry, materials science, biochemistry, molecular biology, and biomedical engineering to develop new analytical tools and in vitro assays to predict and quantify molecular interactions occurring in a cell or within a community of cells.
We are particularly interested in developing new technologies to: i) fabricate arrays of biomolecules in which we could screen drug metabolism in a high-throughput manner; ii) study the response of enzymes and cells to environmental stresses in tissue-like constructs that mimic in vivo conditions. We focus keenly on analytical tools that are amenable to high-throughput screening, are easily assembled or setup, and provide quantitative data.
Nancy Allbritton, the Paul Debreczeny Distinguished Professor of Chemistry and Chair of the UNC/NC State joint Department of Biomedical Engineering, has been named a fellow of the National Academy of Inventors. The honor is awarded to academic inventors who have a prolific spirit of innovation in creating outstanding inventions that have made a tangible impact on quality of life, economic development and the welfare of society. Allbritton was also recently elected a fellow of the American Association for the Advancement of Science, AAAS.
The innovators elected as NAI fellows are named inventors on U.S. patents and were nominated by their peers for outstanding contributions to innovation in areas such as patents and licensing, innovative discovery and technology, significant impact on society, and support and enhancement of innovation.
A new small molecule receptor, A2N, has been identified that binds specifically to trimethyllysine, Kme3, with sub-micromolar affinity. This receptor, as published in Organic & Biomolecular Chemistry was discovered by Nicholas Pinkin and Marcey Waters in the Waters Group, through the iterative redesign of a monomer known to incorporate through dynamic combinatorial chemistry, DCC, into a previously reported receptor for Kme3, A2B. In place of monomer B, the newly designed monomer N introduces an additional cation–Π interaction into the binding pocket, resulting in more favorable binding to Kme3 amounting to a ten-fold improvement in affinity and a five-fold improvement in selectivity over Kme2.
This receptor exhibits the tightest affinity and greatest selectivity for Kme3-containing peptides reported to date. Comparative studies of A2B and A2N provide mechanistic insight into the driving force for both the higher affinity and higher selectivity of A2N, indicating that the binding of Kme3 to A2N is both enthalpically and entropically more favorable. This work demonstrates the ability of iterative redesign coupled with DCC to develop novel selective receptors with the necessary affinity and selectivity required for biological applications.
Light-activatable drugs offer the promise of controlled release with exquisite temporal and spatial resolution. However, light-sensitive prodrugs are typically converted to their active forms using short-wavelength irradiation, which displays poor tissue penetrance. Researchers in the David Lawrence Group report in Angewandte Chemie, International Edition, on erythrocyte-mediated assembly of long-wavelength-sensitive phototherapeutics.
The activating wavelength of the constructs is readily preassigned by using fluorophores with the desired excitation wavelength λex. Drug release from the erythrocyte carrier was confirmed by standard analytical tools and by the expected biological consequences of the liberated drugs in cell culture: methotrexate, binding to intracellular dihydrofolate reductase; colchicine, inhibition of microtubule polymerization; dexamethasone, induced nuclear migration of the glucocorticoid receptor.
As described in Chemical Science, members of the Dempsey Group, in collaboration with the Meyer Group, used a layer-by-layer procedure to prepare chromophore–catalyst assemblies consisting of phosphonate-derivatized porphyrin chromophores and a phosphonate-derivatized ruthenium water oxidation catalyst on the surfaces of tin oxide and titanium dioxide mesoporous, nanoparticle films. In the procedure, initial surface binding of the phosphonate-derivatized porphyrin is followed in sequence by reaction with a zirconium salt and then with the phosphonate-derivatized water oxidation catalyst.
Fluorescence from both the free base and zinc porphyrin derivatives on tin oxide is quenched; substantial emission quenching of the zinc porphyrin occurs on titanium dioxide. Transient absorption difference spectra provide direct evidence for appearance of the porphyrin radical cation on tin oxide via excited-state electron injection. For the chromophore–catalyst assembly on tin oxide, transient absorption difference spectra demonstrate rapid intra-assembly electron transfer oxidation of the catalyst following excitation and injection by the porphyrin chromophore.
Developing novel materials and device architectures to further enhance the efficiency of polymer solar cells requires a fundamental understanding of the impact of chemical structures on photovoltaic properties. Given that device characteristics depend on many parameters, deriving structure/property relationships has been very challenging.
Through an international collaboration, members of the You Group discovered that a single parameter, hole mobility, determines the fill factor of bulk heterojunction photovoltaic devices in a series of copolymers with varying amount of fluorine substitution. The continuous increase of hole mobility upon further fluorination is related to a preferential face-on orientation and improved pi-pi stacking of the polymer backbones. The results shows the potential of properly-designed polymers to enable high fill factors in thick devices, as required by mass production technologies. These significant results appeared in JACS, and were also featured in JACS Spotlights.
Published in Macromolecules, Professor Michael Rubinstein, in collaboration with Ekaterina Zhulina with the Institute of Macromolecular Compounds, Russian Academy of Sciences in Saint Petersburg, describe the development of a scaling model relating the friction forces between two polyelectrolyte brushes sliding over each other to the separation between grafted surfaces, number of monomers and charges per chain, grafting density of chains, and solvent quality. They demonstrate that the lateral force between brushes increases upon compression, but to a lesser extent than the normal force.
The shear stress at larger separations is due to solvent slip layer friction. The thickness of this slip layer sharply decreases at distances on the order of undeformed brush thickness. The corresponding effective viscosity of the layer sharply increases from the solvent viscosity to a much higher value, but this increase is smaller than the jump of the normal force resulting in the drop of the friction coefficient. At stronger compression the group members predict the second sharp increase of the shear stress corresponding to interpenetration of the chains from the opposite brushes. In this regime the velocity-dependent friction coefficient between two partially interpenetrating polyelectrolyte brushes does not depend on the distance between substrates because both normal and shear forces are reciprocally proportional to the plate separation. Although lateral forces between polyelectrolyte brushes are larger than between bare surfaces, the enhancement of normal forces between opposing polyelectrolyte brushes with respect to normal forces between bare charged surfaces is much stronger resulting in lower friction coefficient. The model quantitatively demonstrates how polyelectrolyte brushes provide more effective lubrication than bare charged surfaces or neutral brushes.
At the Department of Chemistry, we feel strongly that diversity is crucial to our pursuit of academic excellence, and we are deeply committed to creating a diverse and inclusive community. We support UNC's policy, which states that "the University of North Carolina at Chapel Hill is committed to equality of opportunity and pledges that it will not practice or permit discrimination in employment on the basis of race, color, gender, national origin, age, religion, creed, disability, veteran's status, sexual orientation, gender identity or gender expression."