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Flavins and Flavoproteins pp 307–340Cite as

Solid-State NMR of Flavins and Flavoproteins

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Part of the book series: Methods in Molecular Biology ((MIMB,volume 1146))

Abstract

Why apply solid-state NMR (SSNMR) to flavins and flavoproteins? NMR provides information on an atom-specific basis about chemical functionality, structure, proximity to other groups, and dynamics of the system. Thus, it has become indispensable to the study of chemicals, materials, catalysts, and biomolecules. It is no surprise then that NMR has a great deal to offer in the study of flavins and flavoenzymes. In general, their catalytic or electron-transfer activity resides essentially in the flavin, a molecule eminently accessible by NMR. However, the specific reactivity displayed depends on a host of subtle interactions whereby the protein biases and reshapes the flavin’s propensities to activate it for one reaction while suppressing other aspects of this cofactor’s prodigious repertoire (Massey et al., J Biol Chem 244:3999–4006, 1969; Müller, Z Naturforsch 27B:1023–1026, 1972; Joosten and van Berkel, Curr Opin Struct Biol 11:195–202, 2007). Thus, we are fascinated to learn about how the flavin cofactor of one enzyme is, and is not, like the flavin cofactor of another. In what follows, we describe how the capabilities of SSNMR can help and are beginning to bear fruit in this exciting endeavor.

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Notes

  1. 1.

    It is anticipated that advanced methods will be undertaken with assistance from experts who will be thoroughly familiar with all material provided here, but the current presentation is intended to provide sufficient background to motivate a collaboration by enabling biochemists to appreciate the opportunities, participate in experimental design, and discuss the results.

  2. 2.

    This relationship between shielding and chemical shift is an approximation that is exact only when the reference signal occurs at a frequency ν ref approaching that of the Larmor frequency, ν 0. When ν ref is far from the Larmor frequency, then δ = 106 × (σ ref − σ obs)/(1 − σ ref) in ppm.

  3. 3.

    The chemical-shift tensor looks like a 3 × 3 matrix whose content depends on what coordinate frame is chosen. However, if we choose a Cartesian frame using the principal axes of the molecule’s shielding as X, Y, and Z axes, the chemical shift tensor will have diagonal elements only and these will be δ 11, δ 22, and δ 33. For further information, see refs. 68, 69.

  4. 4.

    Similar logic applies for aromatic carbons. For the examples of the C(6) and C(9) positions of the flavin xylene ring, coupling of σCH and π* orbitals produces de-shielding tangential to the ring, and coupling of σCC and π* orbitals produces de-shielding radial to the ring, both in the plane of the ring.

  5. 5.

    Müller et al. have popularized the designation of the N(5) and N(1) sites of oxidized flavins as “pyridine-type” nitrogens, consistent with their aromaticity and possession of a non-bonded lone pair in the aromatic plane as in pyridine. The N(3) and N(10) sites, and all four nitrogens of fully reduced flavin have three σ bonds (versus two) and a lone pair roughly perpendicular to the plane of the three bonding partners, as in pyrrole rings so they have been dubbed “pyrrole-type” nitrogens [28]. Because pyrroles are only 5-membered rings and less aromatic, this notation should not be taken too literally [73].

  6. 6.

    For molecules at arbitrary angles, a linear combination of the three principal axes is parallel to the field at one moment, to be replaced with the same linear combination in which the three axes have been permuted in the next. In the end, all three directions will have acquired equal weight regardless of the particular linear combination.

  7. 7.

    The order of the side band is the frequency offset from the isotropic frequency, in units of MAS speed. Higher frequency (down-field) side bands are positive-order bands.

  8. 8.

    For 1H, γ H/(2π) = 42.58 MHz/T, for 19F, γ F/(2π) = 40.05 MHz/T, for 31P, γ P/(2π) = 17.24 MHz/T, for 13C, γ C/(2π) = 10.71 MHz/T, and for 15N, γ N/(2π) = –4.32 MHz/T.

  9. 9.

    Typical dipolar couplings among 13C, 15N, or 31P do not exceed the 13-kHz MAS speeds accessible with routine instrumentation.

  10. 10.

    The ground-state population excess is related by the Boltzmann relation to the energy separating the excited state from the ground state, and the energy separation is proportional to γ. Thus, p n /p 0 = exp[–ΔE/(k B T)], where ΔE = hγB 0/(2π), p n and p 0 are the populations of the excited state and the ground state, ΔE is the energy gap between these two states which for a spin-1/2 nucleus in a magnetic field B 0 is proportional to γ via Planck’s constant h.

  11. 11.

    Due to the several factors that affect the efficiency and maximum amplitude of cross-polarization, the amplitudes of signals observed by this means cannot be related simply to the concentration of corresponding nuclei [71].

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Acknowledgements

I am grateful to the NIH for funding under 1 R01 GM085302-01A1 and to Prof. R. G. Griffin for hospitality at the Francis Bitter Magnet Lab (M.I.T.) during my sabbatical. I also thank S. Pyszczynski and E. Munson for assistance in obtaining spectra of MGA, K. Eichele for generously supplying and supporting his software, and T. Maly for help with Fig. 15. This paper is dedicated to my parents on the occasion of my mother’s 80th birthday.

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  1. Department of Chemistry, University of Kentucky, 505 Rose St, Lexington, KY, 40506-0055, USA

    Anne-Frances Miller

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  1. Anne-Frances Miller
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Correspondence to Anne-Frances Miller .

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  1. Institut für Physikalische Chemie, Albert-Ludwigs-Universität Freiburg, Germany

    Stefan Weber

  2. Institut für Physikalische Chemie, Albert-Ludwigs-Universität Freiburg, Germany

    Erik Schleicher

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Miller, AF. (2014). Solid-State NMR of Flavins and Flavoproteins. In: Weber, S., Schleicher, E. (eds) Flavins and Flavoproteins. Methods in Molecular Biology, vol 1146. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-0452-5_12

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  • DOI: https://doi.org/10.1007/978-1-4939-0452-5_12

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