Burkhard Luy

The dynamic range of the human metabolome revealed by challenges

Metabolic challenge protocols, such as the oral glucose tolerance test, can uncover early alterations in metabolism preceding chronic diseases. Nevertheless, most metabolomics data accessible today reflect the fasting state. To analyze the dynamics of the human metabolome in response to environmental stimuli, we submitted 15 young healthy male volunteers to a highly controlled 4 d challenge protocol, including 36 h fasting, oral glucose and lipid tests, liquid test meals, physical exercise, and cold stress. Blood, urine, exhaled air, and breath condensate samples were analyzed on up to 56 time points by MS‐and NMR‐based methods, yielding 275 metabolic traits with a focus on lipids and amino acids. Here, we show that physiological challenges increased interindividual variation even in phenotypically similar volunteers, revealing metabotypes not observable in baseline metabolite profiles; volunteer‐specific metabolite concentrations were consistently reflected in various biofluids; and readouts from a systematic model of β‐oxidation (e.g., acetylcarnitine/palmitylcarnitine ratio) showed significant and stronger associations with physiological parameters (e.g., fat mass) than absolute metabolite concentrations, indicating that systematic models may aid in understanding individual challenge responses. Due to the multitude of analytical methods, challenges and sample types, our freely available metabolomics data set provides a unique reference for future metabolomics studies and for verification of systems biology models.—Krug, S., Kastenmüller, G., Stückler, F., Rist, M. J., Skurk, T., Sailer, M., Raffler, J., Römisch‐Margl, W., Adamski, J., Prehn, C., Frank, T., Engel, K‐H., Hofmann, T., Luy, B., Zimmermann, R., Moritz, F., Schmitt‐Kopplin, P., Krumsiek, J., Kremer, W., Huber, F., Oeh, U., Theis, F. J., Szymczak, W., Hauner, H., Suhre, K., Daniel, H. The dynamic range of the human metabolome revealed by challenges. FASEB J. 26, 2607‐2619 (2012). www.fasebj.org

Application of optimal control theory to the design of broadband excitation pulses for high-resolution NMR

Optimal control theory is considered as a methodology for pulse sequence design in NMR. It provides the flexibility for systematically imposing desirable constraints on spin system evolution and therefore has a wealth of applications. We have chosen an elementary example to illustrate the capabilities of the optimal control formalism: broadband, constant phase excitation which tolerates miscalibration of RF power and variations in RF homogeneity relevant for standard high-resolution probes. The chosen design criteria were transformation of I(z)-->I(x) over resonance offsets of +/- 20 kHz and RF variability of +/-5%, with a pulse length of 2 ms. Simulations of the resulting pulse transform I(z)-->0.995I(x) over the target ranges in resonance offset and RF variability. Acceptably uniform excitation is obtained over a much larger range of RF variability (approximately 45%) than the strict design limits. The pulse performs well in simulations that include homonuclear and heteronuclear J-couplings. Experimental spectra obtained from 100% 13C-labeled lysine show only minimal coupling effects, in excellent agreement with the simulations. By increasing pulse power and reducing pulse length, we demonstrate experimental excitation of 1H over +/-32 kHz, with phase variations in the spectra <8 degrees and peak amplitudes >93% of maximum. Further improvements in broadband excitation by optimized pulses (BEBOP) may be possible by applying more sophisticated implementations of the optimal control formalism.

The CLIP/CLAP-HSQC: Pure absorptive spectra for the measurement of one-bond couplings

Heteronuclear residual dipolar one-bond couplings of organic molecules at natural abundance are most easily measured using t2 coupled HSQC spectra. However, inevitably mismatched transfer delays result in phase distortions due to residual dispersive antiphase coherences in such experiments. In this article, slightly modified t2 coupled HSQC experiments with clean inphase (CLIP) multiplets are introduced which also reduce the intensities of undesired long-range cross peaks. With the corresponding antiphase (CLAP) experiment, situations where alpha and beta components overlap can be resolved for all multiplicities in an IPAP manner. A comparison of the experiments using hard pulses and shaped broadband excitation and inversion pulses on the heteronucleus is given and potential spectral artefacts are discussed in detail.

Residual Dipolar Couplings for the Configurational and Conformational Analysis of Organic Molecules

Abstract Residual dipolar couplings (RDCs) have already revolutionized biomolecular NMR spectroscopy and are about to do the same in small molecule applications: impressive examples for conformational refinement of small sugars and peptides, the distinction of enantiomers and the determination of relative and absolute configuration have been published in recent years. After a short introduction into the basic theory, this article will give a review of existing alignment media, methods for scaling the alignment, pulse sequences for measuring RDCS and recent applications.

Optimal control of spin dynamics in the presence of relaxation

Experiments in coherent spectroscopy correspond to control of quantum mechanical ensembles guiding them from initial to final target states. The control inputs (pulse sequences) that accomplish these transformations should be designed to minimize the effects of relaxation and to optimize the sensitivity of the experiments. For example in nuclear magnetic resonance (NMR) spectroscopy, a question of fundamental importance is what is the maximum efficiency of coherence or polarization transfer between two spins in the presence of relaxation. Furthermore, what is the optimal pulse sequence which achieves this efficiency? In this paper, we give analytical answers to the above questions. Unexpected gains in sensitivity are reported for one of the most commonly used experimental building blocks in NMR spectroscopy. Surprisingly, in the case when longitudinal relaxation is small, the relaxation optimized pulse elements (ROPE) that transfer maximum polarization between coupled spins are longer than conventional sequences.

Boundary of quantum evolution under decoherence

Relaxation effects impose fundamental limitations on our ability to coherently control quantum mechanical phenomena. In this article, we use principles of optimal control theory to establish physical limits on how closely a quantum mechanical system can be steered to a desired target state in the presence of relaxation. In particular, we explicitly compute the maximum amplitude of coherence or polarization that can be transferred between coupled heteronuclear spins in large molecules at high magnetic fields in the presence of relaxation. Very general decoherence mechanisms that include cross-correlated relaxation have been included in our analysis. We give analytical characterization for the pulse sequences (control laws) that achieve these physical limits and provide supporting experimental evidence. Exploitation of cross-correlation effects has recently led to the development of powerful methods in NMR spectroscopy to study very large biomolecules in solution. For two heteronuclear spins, we demonstrate with experiments that cross-correlated relaxation optimized pulse (CROP) sequences provide significant gains over the state-of-the-art methods. It is shown that despite large relaxation rates, coherence can be transferred between coupled spins without any loss in special cases where cross-correlated relaxation rates can be tuned to autocorrelated relaxation rates.

Training Schrödinger’s cat: quantum optimal control

It is control that turns scientific knowledge into useful technology: in physics and engineering it provides a systematic way for driving a dynamical system from a given initial state into a desired target state with minimized expenditure of energy and resources. As one of the cornerstones for enabling quantum technologies, optimal quantum control keeps evolving and expanding into areas as diverse as quantum-enhanced sensing, manipulation of single spins, photons, or atoms, optical spectroscopy, photochemistry, magnetic resonance (spectroscopy as well as medical imaging), quantum information processing and quantum simulation. In this communication, state-of-the-art quantum control techniques are reviewed and put into perspective by a consortium of experts in optimal control theory and applications to spectroscopy, imaging, as well as quantum dynamics of closed and open systems. We address key challenges and sketch a roadmap for future developments.

Structure refinement of cyclosporin A in chloroform by using RDCs measured in a stretched PDMS-gel.

New developments concerning alignment media for apolar solvents like chloroform make it possible to measure anisotropic parameters such as residual dipolar couplings (RDCs) at relatively low concentrations and natural isotopic abundance. As RDCs provide structural restraints with respect to an external coordinate system, long‐range structural arrangements of the time‐averaged structure can be determined with high precision. The method is demonstrated on the well‐studied cyclo‐undecapeptide Cyclosporin A (CsA), for which crystal and conventionally derived NMR structures are available. Neither crystal nor NMR structure are consistent with heteronuclear DCH RDCs measured in a stretched poly(dimethylsiloxane) gel, and refinement by using the anisotropic parameter results in a highly defined structure with a slightly changed backbone conformation. The applied methods and interpretation of the structural model are discussed.

Exploring the limits of broadband excitation and inversion: II. Rf-power optimized pulses

In [K. Kobzar, T.E. Skinner, N. Khaneja, S.J. Glaser, B. Luy, Exploring the limits of broadband excitation and inversion, J. Magn. Reson. 170 (2004) 236-243], optimal control theory was employed in a systematic study to establish physical limits for the minimum rf-amplitudes required in broadband excitation and inversion pulses. In a number of cases, however, experimental schemes are not limited by rf-amplitudes, but by the overall rf-power applied to a sample. We therefore conducted a second systematic study of excitation and inversion pulses of varying pulse durations with respect to bandwidth and rf-tolerances, but this time using a modified algorithm involving restricted rf-power. The resulting pulses display a variety of pulse shapes with highly modulated rf-amplitudes and generally show better performance than corresponding pulses with identical pulse length and rf-power, but limited rf-amplitude. A detailed description of pulse shapes and their performance is given for the so-called power-BEBOP and power-BIBOP pulses.

Residual Dipolar Couplings as a Powerful Tool for Constitutional Analysis: The Unexpected Formation of Tricyclic Compounds

Anisotropic NMR parameters in partially aligned samples, such as residual dipolar couplings (RDCs), residual chemical shift anisotropy (RCSA), and residual quadrupolar couplings (RQCs), contain valuable structural information. As has been shown on a multitude of examples, RDCs are a useful tool to determine the configuration and the conformation of small to medium-sized organic molecules. Herein, we now add a further facet by demonstrating the power of RDCs in the analysis of the constitution of an unknown small molecule. The molecule we investigated in this case study is one of the products obtained by reacting the azide-containing 1,5enyne 1 in the presence of electrophilic iodine sources (Scheme 1). Recently, it was reported that enyne 1 (R =