Project description:Recent advances in bioorthogonal catalysis are increasing the capacity of researchers to manipulate the fate of molecules in complex biological systems. A bioorthogonal uncaging strategy is presented, which is triggered by heterogeneous gold catalysis and facilitates the activation of a structurally diverse range of therapeutics in cancer cell culture. Furthermore, this solid-supported catalytic system enabled locally controlled release of a fluorescent dye into the brain of a zebrafish for the first time, offering a novel way to modulate the activity of bioorthogonal reagents in the most fragile and complex organs.
Project description:Bioorthogonal cleavage chemistry has been rapidly emerging as a powerful tool for manipulation and gain-of-function studies of biomolecules in living systems. While the initial bond formation-centered bioorthogonal reactions have been widely adopted for labeling, tracing, and capturing biomolecules, the newly developed bond cleavage-enabled bioorthogonal reactions have opened new possibilities for rescuing small molecules as well as biomacromolecules in living systems, allowing multidimensional controls over biological processes in vitro and in vivo. In this Outlook, we first summarized the development and applications of bioorthogonal cleavage reactions (BCRs) that restore the functions of chemical structures as well as more complex networks, including the liberation of prodrugs, release of bioconjugates, and in situ reactivation of intracellular proteins. As we embarked on this fruitful progress, we outlined the unmet scientific needs and future directions along this exciting avenue. We believe that the potential of BCRs will be further unleashed when combined with other frontier technologies, such as genetic code expansion and proximity-enabled chemical labeling.
Project description:Organofluorines represent a rapidly expanding proportion of molecules that are used in pharmaceuticals, diagnostics, agrochemicals, and materials. Despite the prevalence of fluorine in synthetic compounds, the known biological scope is limited to a single pathway that produces fluoroacetate. Here, we demonstrate that this pathway can be exploited as a source of fluorinated building blocks for introduction of fluorine into natural-product scaffolds. Specifically, we have constructed pathways involving two polyketide synthase systems, and we show that fluoroacetate can be used to incorporate fluorine into the polyketide backbone in vitro. We further show that fluorine can be inserted site-selectively and introduced into polyketide products in vivo. These results highlight the prospects for the production of complex fluorinated natural products using synthetic biology.
Project description:Quantum control of chemical reactions is an important goal in chemistry and physics. Ultracold chemical reactions are often controlled by preparing the reactants in specific quantum states. Here we demonstrate spin-controlled atom-ion inelastic (spin-exchange) processes and chemical (charge-exchange) reactions in an ultracold Rb-Sr+ mixture. The ion's spin state is controlled by the atomic hyperfine spin state via spin-exchange collisions, which polarize the ion's spin parallel to the atomic spin. We achieve ~ 90% spin polarization due to the absence of strong spin-relaxation channel. Charge-exchange collisions involving electron transfer are only allowed for (RbSr)+ colliding in the singlet manifold. Initializing the atoms in various spin states affects the overlap of the collision wave function with the singlet molecular manifold and therefore also the reaction rate. Our observations agree with theoretical predictions.
Project description:We present a composite procedure for the quantum-chemical computation of spin-spin-coupled 1 H NMR spectra for general, flexible molecules in solution that is based on four main steps, namely conformer/rotamer ensemble (CRE) generation by the fast tight-binding method GFN-xTB and a newly developed search algorithm, computation of the relative free energies and NMR parameters, and solving the spin Hamiltonian. In this way the NMR-specific nuclear permutation problem is solved, and the correct spin symmetries are obtained. Energies, shielding constants, and spin-spin couplings are computed at state-of-the-art DFT levels with continuum solvation. A few (in)organic and transition-metal complexes are presented, and very good, unprecedented agreement between the theoretical and experimental spectra was achieved. The approach is routinely applicable to systems with up to 100-150 atoms and may open new avenues for the detailed (conformational) structure elucidation of, for example, natural products or drug molecules.
Project description:Chemical reactions that enable selective biomolecule labeling in living organisms offer a means to probe biological processes in vivo. Very few reactions possess the requisite bioorthogonality, and, among these, only the Staudinger ligation between azides and triarylphosphines has been employed for direct covalent modification of biomolecules with probes in the mouse, an important model organism for studies of human disease. Here we explore an alternative bioorthogonal reaction, the 1,3-dipolar cycloaddition of azides and cyclooctynes, also known as "Cu-free click chemistry," for labeling biomolecules in live mice. Mice were administered peracetylated N-azidoacetylmannosamine (Ac(4)ManNAz) to metabolically label cell-surface sialic acids with azides. After subsequent injection with cyclooctyne reagents, glycoconjugate labeling was observed on isolated splenocytes and in a variety of tissues including the intestines, heart, and liver, with no apparent toxicity. The cyclooctynes tested displayed various labeling efficiencies that likely reflect the combined influence of intrinsic reactivity and bioavailability. These studies establish Cu-free click chemistry as a bioorthogonal reaction that can be executed in the physiologically relevant context of a mouse.
Project description:Many spintronics applications consist of ultrathin magnetic and nonmagnetic multilayers and require an in-depth understanding of interfacial magnetism and spin transport. Here, we study permalloy/copper/platinum multilayer systems. We find that magnetic damping, perpendicular anisotropy, and proximity magnetization exhibit correlated oscillations as a function of the copper thickness. We ascribe these observations to an oscillatory interlayer coupling between permalloy and platinum. Such interlayer coupling may have a significant impact on the performance of spintronics applications.
Project description:The spin-textures of bound medium-body systems with spin-[Formula: see text] atoms ([Formula: see text]) have been studied. The Hamiltonian is assumed to be dominated by the two-body interaction favoring parallel spins. The system with particle number [Formula: see text] and [Formula: see text] is first chosen, and the Hamiltonian is exactly diagonalized by using Fock-states as basis-states, thereby all the eigenenergies and eigenstates are obtained and a detailed analysis is made. Then the cases with [Formula: see text] and [Formula: see text] are further studied. Since the total spin S is conserved, the eigenstates having the same S form an S-group. Let the lowest (highest) energy state of an S-group be called a bottom-state (top-state). We found that all the bottom-states are bipartite product states with constituent states describing fully polarized subsystems containing [Formula: see text] and [Formula: see text] ([Formula: see text]) particles, respectively. For two bottom-states different in [Formula: see text], the one with a larger [Formula: see text] is higher. For two having the same [Formula: see text], the one with a smaller S is higher. Whereas all the top-states are found to be essentially a product state of the pairs, in each pair the two spins are coupled to [Formula: see text] if the strength of the [Formula: see text]-channel is more repulsive than the others. For the states belonging to an S-group, the higher one would contain more pieces. As the energy goes up, larger pieces (those containing more than two particles) will disappear.
Project description:We present a protocol based on unitary transformations of molecular orbitals to reduce the number of nonvanishing coefficients of spin-adapted configuration interaction expansions. Methods that exploit the sparsity of the Hamiltonian matrix and compactness of its eigensolutions, such as the full configuration interaction quantum Monte Carlo (FCIQMC) algorithm in its spin-adapted implementation, are well suited to this protocol. The wave function compression resulting from this approach is particularly attractive for antiferromagnetically coupled polynuclear spin systems, such as transition-metal cubanes in biocatalysis, and Mott and charge-transfer insulators in solid-state physics. Active space configuration interaction calculations on N2 and CN- at various bond lengths, the stretched square N4 compounds, the chromium dimer, and a [Fe2S2]2- model system are presented as a proof-of-concept. For the Cr2 case, large and intermediate bond distances are discussed, showing that the approach is effective in cases where static and dynamic correlations are equally important. The [Fe2S2]2- case shows the general applicability of the method.
Project description:EPR spectroscopy of diamagnetic bio-macromolecules is based on site-directed spin labeling (SDSL). Herein, a novel labeling strategy for proteins is presented. A nitroxide-based spin label has been developed and synthesized that can be ligated to proteins by an inverse-electron-demand Diels-Alder (DAinv ) cycloaddition to genetically encoded noncanonical amino acids. The nitroxide moiety is shielded by a photoremovable protecting group with an attached tetra(ethylene glycol) unit to achieve water solubility. SDSL is demonstrated on two model proteins with the photoactivatable nitroxide for DAinv reaction (PaNDA) label. The strategy features high reaction rates, combined with high selectivity, and the possibility to deprotect the nitroxide in Escherichia coli lysate.