1,721,055 research outputs found
Nuclear spin singlet states as magnetic on/off probes in self-assembling systems
Full text linkSelf-assembling processes occur in a variety of compounds such as peptides, proteins and DNA. These processes have been linked to pathologies and have as well been exploited for designing responsive contrast agents for disease detection. Novel methods to investigate and detect self-assembly therefore hold promise to obtain more insights into disease progression or open pathways to the design of novel self-assembling materials. In this article we are introducing nuclear singlet states to probe self-assembly in the dipeptide isoleucine–phenylalanine (IF) as a thermoresponsive on/off switch for nuclear magnetic resonance (NMR). We have investigated the relaxation and singlet state properties of the β-protons of phenylalanine in the IF dipeptide in aqueous solutions. At IF concentrations of 2 wt% and above 308 K, a long lived nuclear singlet state, as compared to the longitudinal relaxation, was observed. At 308 K the dipeptide starts forming a gel and no singlet state is accessible at lower temperatures. Upon heating, the gel disassembles and an isotropic liquid forms making the singlet state accessible again. This demonstrates the thermoresponsive on–off character of the nuclear spin singlet state in the IF dipeptide
Molecular precursors to produce para-hydrogen enhanced metabolites at any field
No full textEnhancing magnetic resonance signal via hyperpolarization techniques enables the real-time detection of metabolic transformations even in vivo. The use of para-hydrogen to enhance 13C-enriched metabolites has opened a rapid pathway for the production of hyperpolarized metabolites, which usually requires specialized equipment. Metabolite precursors that can be hyperpolarized and converted into metabolites at any given field would open up opportunities for many labs to make use of this technology because already existing hardware could be used. We report here on the complete synthesis and hyperpolarization of suitable precursor molecules of the side-arm hydrogenation approach. The better accessibility to such side-arms promises that the para-hydrogen approach can be implemented in every lab with existing two channel NMR spectrometers for 1H and 13C independent of the magnetic field
Nuclear singlet multimers (NUSIMERs) with long-lived singlet states
No full textMagnetic resonance (NMR) is a powerful tool in chemical analysis, structure determination and in medical diagnostics. Developing novel biological sensors for this field holds promise to better investigate protein structures or target diseases more efficiently. Herein, we explore nuclear spin singlet states in dendritic macromolecules as a platform molecule to develop stimuli responsive probes. We have developed a nuclear singlet multimer (NUSIMER) based on a generation 5 poly(amidoamine) dendrimer (PAMAM) which contains on average about 90 accessible nuclear spin singlet states with lifetimes up to 10-fold longer than the T1 relaxation times (up to 10 seconds Tsvs. T1 < 0.5 seconds) in a single molecule. We demonstrate little influence on the singlet lifetime in phosphate buffer (H2O) and a high viscosity gel environment in the presence of paramagnetic oxygen. Additionally, we demonstrate an increase in singlet lifetime upon the release of a protective chemical moiety from the NUSIMER following a stimulus, whereby no change in longitudinal relaxation time is observed. The robustness and change in singlet lifetime of the NUSIMER holds promise for the development of a novel type of biosensors
Pulsed magnetic resonance to signal‐enhance metabolites within seconds by utilizing para‐hydrogen
Full text linkDiseases such as Alzheimer's and cancer have been linked to metabolic dysfunctions, and further understanding of metabolic pathways raises hope to develop cures for such diseases. To broaden the knowledge of metabolisms in vitro and in vivo, methods are desirable for direct probing of metabolic function. Here, we are introducing a pulsed nuclear magnetic resonance (NMR) approach to generate hyperpolarized metabolites within seconds, which act as metabolism probes. Hyperpolarization represents a magnetic resonance technique to enhance signals by over 10 000‐fold. We accomplished an efficient metabolite hyperpolarization by developing an isotopic labeling strategy for generating precursors containing a favorable nuclear spin system to add para‐hydrogen and convert its two‐spin longitudinal order into enhanced metabolite signals. The transfer is performed by an invented NMR experiment and 20 000‐fold signal enhancements are achieved. Our technique provides a fast way of generating hyperpolarized metabolites by using para‐hydrogen directly in a high magnetic field without the need for field cycling
Orientational Sampling Schemes Based on Four Dimensional Polytopes
No full textThe vertices of regular four-dimensional polytopes are used to generate sets of uniformly distributed three-dimensional rotations, which are provided as tables of Euler angles. The spherical moments of these orientational sampling schemes are treated using group theory. The orientational sampling sets may be used in the numerical computation of solid-state nuclear magnetic resonance spectra, and in spherical tensor analysis procedures
Over 50 %1H and 13C polarization for generating hyperpolarized metabolites—A para‐hydrogen approach.
Full text linkpara‐Hydrogen‐induced polarization (PHIP) is a method to rapidly generate hyperpolarized compounds, enhancing the signal of nuclear magnetic resonance (NMR) experiments by several thousand‐fold. The hyperpolarization of metabolites and their use as contrast agents in vivo is an emerging diagnostic technique. High degrees of polarization and extended polarization lifetime are necessary requirements for the detection of metabolites in vivo. Here, we present pulsed NMR methods for obtaining hyperpolarized magnetization in two metabolites. We demonstrate that the hydrogenation with para‐hydrogen of perdeuterated vinyl acetate allows us to create hyperpolarized ethyl acetate with close to 60 % 1H two‐spin order. With nearly 100 % efficiency, this order can either be transferred to 1H in‐phase magnetization or 13C magnetization of the carbonyl function. Close to 60 % polarization is experimentally verified for both nuclei. Cleavage of the ethyl acetate precursor in a 20 s reaction yields ethanol with approximately 27 % 1H polarization and acetate with around 20 % 13C polarization. This development will open new opportunities to generate metabolic contrast agents in less than one minute
Bimodal Fluorescence/Magnetic Resonance Molecular Probes with Extended Spin Lifetimes
Full text linkBimodal molecular probes combining nuclear magnetic resonance (NMR) and fluorescence have been widely studied in basic science, as well as clinical research. The investigation of spin phenomena holds promise to broaden the scope of available probes allowing deeper insights into physiological processes. Herein, a class of molecules with a bimodal character with respect to fluorescence and nuclear spin singlet states is introduced. Singlet states are NMR silent but can be probed indirectly. Symmetric, perdeuterated molecules, in which the singlet states can be populated by vanishingly small electron-mediated couplings (below 1 Hz) are reported. The lifetimes of these states are an order of magnitude longer than the longitudinal relaxation times and up to four minutes at 7 T. Moreover, these molecules show either aggregation induced emission (AIE) or aggregation caused quenching (ACQ) with respect to their fluorescence. In the latter case, the existence of excited dimers, which are proposed to use in a switchable manner in combination with the quenching of nuclear spin singlet states, is observed
Accurate Determination of 1H-15N Dipolar Couplings Using Inaccurate Settings of the Magic Angle in Solid-State NMR Spectroscopy
No full textMagic-angle spinning (MAS) is an essential ingredient in a wide variety of solid-state NMR experiments. The standard procedures to adjust the rotor angle are not highly accurate, resulting in a slight misadjustment of the rotor from the magic angle (θRL = tan-1 √2) on the order of a few millidegrees. This small missetting has no significant impact on the overall spectral resolution, but is sufficient to reintroduce anisotropic interactions. Shown here is that site-specific 1H-15N dipolar couplings can be accurately measured in a heavily deuterated protein. This method can be applied at arbitrarily high MAS frequencies, since neither rotor synchronization nor particularly high radiofrequency field strengths are required. The off-MAS method allows the quantification of order parameters for very dynamic residues, which often escape an analysis using existing methods
Early Divergence in Misfolding Pathways of Amyloid-Beta Peptides
Full text linkThe amyloid cascade hypothesis proposes that amyloid-beta (Aβ) aggregation is the initial triggering event in Alzheimer's disease. Here, we utilize NMR spectroscopy and monitor the structural dynamics of two variants of Aβ, Aβ40 and Aβ42, as a function of temperature. Despite having identical amino acid sequence except for the two additional C-terminal residues, Aβ42 has higher aggregation propensity than Aβ40. As revealed by the NMR data on dynamics, including backbone chemical shifts, intra-methyl cross-correlated relaxation rates and glycine-based singlet-states, the C-terminal region of Aβ, especially the G33-L34-M35 segment, plays a particular role in the early steps of temperature-induced Aβ aggregation. In Aβ42, the distinct dynamical behaviour of C-terminal residues at higher temperatures is accompanied with marked changes in the backbone dynamics of residues V24-K28. The distinctive role of the C-terminal region of Aβ42 in the initiation of aggregation defines a target for the rational design of Aβ42 aggregation inhibitors
Determination of methyl order parameters using solid state NMR under off magic angle spinning
No full textQuantification of dipolar couplings in biological solids is important for the understanding of dynamic processes. Under Magic Angle Spinning (MAS), order parameters are normally obtained by recoupling of anisotropic interactions involving the application of radio frequency pulses. We have recently shown that amide backbone order parameters can be estimated accurately in a spin-echo experiment in case the rotor spinning angle is slightly mis-calibrated. In this work, we apply this method to determine methyl order parameters in a deuterated sample of the SH3 domain of chicken α-spectrin in which the methyl containing side chains valine and leucine are selectively protonated
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