Genetically encoded protein scaffolds often serve as templates for the mineralization of biocomposite materials with complex yet highly controlled structural features that span from nanometres to the macroscopic scale. Methods developed to mimic these fabrication capabilities can produce synthetic materials with well defined micro- and macro-sized features, but extending control to the nanoscale remains challenging. DNA nanotechnology can deliver a wide range of customized nanoscale two- and three-dimensional assemblies with controlled sizes and shapes. But although DNA has been used to modulate the morphology of inorganic materials and DNA nanostructures have served as moulds and templates, it remains challenging to exploit the potential of DNA nanostructures fully because they require high-ionic-strength solutions to maintain their structure, and this in turn gives rise to surface charging that suppresses the material deposition. Here we report that the Stöber method, widely used for producing silica (silicon dioxide) nanostructures, can be adjusted to overcome this difficulty: when synthesis conditions are such that mineral precursor molecules do not deposit directly but first form clusters, DNA-silica hybrid materials that faithfully replicate the complex geometric information of a wide range of different DNA origami scaffolds are readily obtained. We illustrate this approach using frame-like, curved and porous DNA nanostructures, with one-, two- and three-dimensional complex hierarchical architectures that range in size from 10 to 1,000 nanometres. We also show that after coating with an amorphous silica layer, the thickness of which can be tuned by adjusting the growth time, hybrid structures can be up to ten times tougher than the DNA template while maintaining flexibility. These findings establish our approach as a general method for creating biomimetic silica nanostructures.
Structured water molecules near redox cofactors were found recently to accelerate electrontransfer (ET) kinetics in several systems. Theoretical study of interprotein electron transfer across an aqueous interface reveals three distinctive electronic coupling mechanisms that we describe here: (i) a protein-mediated regime when the two proteins are in van der Waals contact; (ii) a structured water-mediated regime featuring anomalously weak distance decay at relatively close protein-protein contact distances; and (iii) a bulk water-mediated regime at large distances. Our analysis explains a range of otherwise puzzling biological ET kinetic data and provides a framework for including explicit water-mediated tunneling effects on ET kinetics.Protein ET reactions play a critical role in biologically vital processes in living cells, most notably photosynthesis and respiration (1). Describing the structure dependence of intermolecular ET reactions is particularly challenging because of the wide range of the accessible docking geometries, and several studies have addressed these reaction mechanisms (2-8). The factors that control unimolecular ET rates, namely the donor-toacceptor (D to A) distance and energies, the structure of the ET-mediating protein matrix, and the thermal atomic motion, have been extensively explored both experimentally (4-6) and theoretically (9-14).Intermolecular ET reactions, however, remain a challenge. In addition to the above factors, the rate depends on the D-to-A docking geometry, as well as on the structure and thermal motion of the solvent (2-7). The number of structural degrees of freedom makes quantitatively reliable theoretical calculations extremely difficult. We show that the intervening water structure leads to one of three distinctly different ET tunneling regimes, in contrast to the common assumption of single-exponential distance decay (2, 5-7). The identification of these three regimes provides a framework for understanding the mechanisms that underlie several unexplained and seemingly unrelated water-mediated biological ET rate processes (7,(15)(16)(17)(18)(19), as well as providing a strategy for making theoretical estimates of bimolecular rates that take these water-mediation effects into account.Water can influence the ET reaction rates by mediating ET coupling pathways, as well as by controlling activation free energies (5, 9). In the past decade, the distance dependence of water-mediated ET reaction rates has become the focus of intensive experimental (4-7, 13, * To whom correspondence should be addressed: david.beratan@duke.edu. 15-17, 20, 21) and theoretical (18, 19, 22-24) investigation. Until recently, experimental and theoretical analysis suggested a single-exponential decay of the ET rates with distance through water, with a characteristic decay constant of about 1.6 to 1.7 Å −1 (5,20,21). In comparison with proteins that exhibit decay constants of about 1.0 to 1.2 Å −1 (5), water appeared to be a rather poor ET mediator because of extensive through-space link...
Small molecules that can selectively target cancer stem cells (CSCs) remain rare currently and exhibit no common structural features. Here we report a series of guaianolide sesquiterpene lactones (GSLs) and their derivatives that can selectively eradicate acute myelogenous leukemia (AML) stem or progenitor cells. Natural GSL compounds arglabin, an anticancer clinical drug, and micheliolide (MCL), are able to reduce the proportion of AML stem cells (CD34⁺CD38⁻) in primary AML cells. Targeting of AML stem cells is further confirmed by a sharp reduction of colony-forming units of primary AML cells upon MCL treatment. Moreover, DMAMCL, the dimethylamino Michael adduct of MCL, slowly releases MCL in plasma and in vivo and demonstrates remarkable therapeutic efficacy in the nonobese diabetic/severe combined immunodeficiency AML models. These findings indicate that GSL is an ample source for chemical agents against AML stem or progenitor cells and that GSL is potentially highly useful to explore anti-CSC approaches.
Acetyl-CoA is a fundamental metabolite for all life on Earth, and is also a key starting point for the biosynthesis of a variety of industrial chemicals and natural products. Here we design and construct a Synthetic Acetyl-CoA (SACA) pathway by repurposing glycolaldehyde synthase and acetyl-phosphate synthase. First, we design and engineer glycolaldehyde synthase to improve catalytic activity more than 70-fold, to condense two molecules of formaldehyde into one glycolaldehyde. Second, we repurpose a phosphoketolase to convert glycolaldehyde into acetyl-phosphate. We demonstrated the feasibility of the SACA pathway in vitro, achieving a carbon yield ~50%, and confirmed the SACA pathway by 13C-labeled metabolites. Finally, the SACA pathway was verified by cell growth using glycolaldehyde, formaldehyde and methanol as supplemental carbon source. The SACA pathway is proved to be the shortest, ATP-independent, carbon-conserving and oxygen-insensitive pathway for acetyl-CoA biosynthesis, opening possibilities for producing acetyl-CoA-derived chemicals from one-carbon resources in the future.
The inherent specificity of DNA sequence hybridization has been extensively exploited to develop bioengineering applications. Nevertheless, the structural potential of DNA has been far less explored for creating non-canonical DNA-based reactions. Here we develop a DNA origami-enabled highly localized metallization reaction for intrinsic metallization patterning with 10-nm resolution. Both theoretical and experimental studies reveal that low-valence metal ions (Cu2+ and Ag+) strongly coordinate with DNA bases in protruding clustered DNA (pcDNA) prescribed on two-dimensional DNA origami, which results in effective attraction within flexible pcDNA strands for site-specific pcDNA condensation. We find that the metallization reactions occur selectively on prescribed sites while not on origami substrates. This strategy is generically applicable for free-style metal painting of alphabet letters, digits and geometric shapes on all−DNA substrates with near-unity efficiency. We have further fabricated single- and double-layer nanoscale printed circuit board (nano-PCB) mimics, shedding light on bio-inspired fabrication for nanoelectronic and nanophotonic applications.
An efficient directed evolution strategy for enhancing activity and manipulating stereoselectivity of a monoamine oxidase is presented.
Calcium phosphate (CaP) nanocrystals with prescribed geometric structures are constructed using various DNA frameworks as templates. Synchrotron small angle X-ray scattering (SAXS) data reveal the initial crystallization process by DNA frameworks. Further experimental studies and theoretical calculations demonstrate that by encoding DNA frameworks via sequence design, one can rationally control the size and shape of CaP nanostructures. These preliminary findings would enlighten the design and applications of DNA framework-encoded biomimetic mineralization and organic-inorganic composite materials.
BackgroundIn silico target prediction of compounds plays an important role in drug discovery. The chemical similarity ensemble approach (SEA) is a promising method, which has been successfully applied in many drug-related studies. There are various models available analogous to SEA, because this approach is based on different types of molecular fingerprints. To investigate the influence of training data selection and the complementarity of different models, several SEA models were constructed and tested.ResultsWhen we used a test set of 37,138 positive and 42,928 negative ligand-target interactions, among the five tested molecular fingerprint methods, at significance level 0.05, Topological-based model yielded the best precision rate (83.7 %) and (0.784) while Atom pair-based model yielded the best (0.694). By employing an election system to combine the five models, a flexible prediction scheme was achieved with precision range from 71 to 90.6 %, range from 0.663 to 0.684 and range from 0.696 to 0.817.ConclusionsThe overall effectiveness of all of the five models could be ranked in decreasing order as follows: Atom pair Topological > Morgan > MACCS > Pharmacophore. Combining multiple SEA models, which takes advantages of different models, could be used to improve the success rates of the models. Another possibility of improving the model could be using target-specific classes or more active compounds.Electronic supplementary materialThe online version of this article (doi:10.1186/s13321-016-0130-x) contains supplementary material, which is available to authorized users.
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