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Solid-State NMR Spectroscopy Molecular Structure and Organization at the Atomic Level.

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Highlights
DOI: 10.1002/anie.200503223
Solid-State NMR Spectroscopy
Solid-State NMR Spectroscopy: Molecular Structure and
Organization at the Atomic Level
Marc Baldus*
Keywords:
fibers · NMR spectroscopy · polymorphism ·
X-ray diffraction · zeolites
Understanding structural organization
in densely packed molecular assemblies
is a central objective of current structural biology and nanotechnology. Solidstate nuclear magnetic resonance
(ssNMR) spectroscopy is a spectroscopic method ideally suited to study structure and dynamics in such systems at the
atomic level. For example, ssNMR has
been extensively used to understand
why compounds of low molecular
weight can occur simultaneously in different solid forms. Such polymorphic
systems often given rise to distinct solidstate NMR resonance frequencies.[1] In
addition, ssNMR is a powerful tool to
study ring-current effects and hydrogenbond interactions that can be of crucial
importance in supramolecular structure
and organization.[2]
Access to high-field ssNMR instruments, advancements in solid-state
NMR methodology, and novel sample
preparation and isotope labeling techniques have significantly expanded the use
of solid-state NMR spectroscopy. A
principal challenge has been to assemble
complete three-dimensional molecular
structures from ssNMR data using a
single sample or a small number of
compounds under MAS (magic angle
spinning[3]) conditions. These difficulties
are intimately related to the dominant
influence of nearest-neighbor dipole–
dipole interactions that are usually of
[*] Dr. M. Baldus
Max-Planck-Institut f6r Biophysikalische
Chemie
Abteilung f6r NMR-Basierte
Strukturbiologie
37077 G<ttingen (Germany)
Fax: (+ 49) 551-201-2212
E-mail: maba@mpibpc.mpg.de
1186
limited structural relevance and obscure
the precise measurement of weak interactions that encode information about
the 3D molecular arrangement.
Recently,
complementary
approaches to circumvent these problems
have been proposed. Firstly, the spin
network can be diluted by chemicalshift-selective pulse schemes[4] or by
tailored chemical synthesis[5, 6] (Figure 1 a). In addition, the direct[6, 7] or
indirect[8] detection of proton–proton
interactions (Figure 1 b) has been shown
to deliver structural constraints useful
for the determination of complete 3D
molecular structures. If the conformation of the monomer is known, these
methods can also be used to characterize
supramolecular organization.[9]
Ideally, ssNMR methods should provide simultaneously information about
the local molecular conformation and
the macromolecular arrangement of the
system of interest. Levitt and co-workers[10] have now shown that both aspects
can be addressed by monitoring dipolar
interactions in a naturally diluted spin
network (Figure 1 c). For this purpose,
zeolite frameworks were investigated by
two-dimensional (2D) high-resolution
29
Si ssNMR spectroscopy. In general,
dipolar-coupled spin pairs are conveniently detected in a double-quantum
(2Q) filtered correlation experiment
Figure 1. Three approaches to determine molecular structures by high-resolution solid-state
NMR spectroscopy ranging from material-science applications to proteins. To overcome strong
coupling conditions (top), a dilution of the spin network can be achieved by chemical-shiftselective pulse schemes or by tailored chemical synthesis (a); NMR-active nuclei are in gray. In
addition, proton–proton interactions (b) report on 3D molecular structure. Levitt and coworkers[10] recently showed that structure and supramolecular organization can also be inferred
from monitoring dipolar interactions in a naturally diluted spin network (c).
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2006, 45, 1186 – 1188
Angewandte
Chemie
that separates out ssNMR signals of spin
pairs found in close spatial proximity.[11]
Because of the natural abundance of 29Si
of 4.7 %, a significant number of isolated
29
Si–29Si spin pairs are distributed
throughout the zeolite structure. Unlike
the case of a densely coupled spin
network where the spin dynamics are
dominated by the strongest interaction,
the intensity of a 2Q signal for a given
mixing time directly reports on the
distribution of Si–Si distances. While
for short mixing times, 2Q signals arise
primarily from 29Si–29Si spin pairs across
the Si-O-Si linkages, longer distances
(up to 8 = according to Ref. [10]) contribute to 2Q intensities seen for mixing
times between 10 and 32 ms. Using a
series of two-dimensional double-quantum, single-quantum (2Q,1Q) correlation experiments, Si–Si distance distributions can be mapped out for each
(2Q,1Q) correlation.
Firstly, Levitt et al.[10] showed that
the 29Si 2Q build-up curves are highly
sensitive to the Si–Si internuclear distance and can be faithfully simulated if
the supramolecular arrangement is
known. On the basis of these findings,
they more recently discussed how these
correlations can be combined with
knowledge about unit-cell parameters
and space group to solve structural
models that refine successfully against
the powder X-ray diffraction (XRD)
data (Figure 2 a). Briefly, the corresponding algorithm is tailored to find a
set of Si atomic coordinates in the
asymmetric unit that minimizes the
sum of the squares of the residuals
between the experimental 2Q curves
and the 2Q curves calculated from the
set of Si–Si distances for a given arrangement of Si atoms. Candidate structures are built up by using one Si site at a
time consistent with the atomic coordinates of the asymmetric unit. Final
candidate structures that meet the occupancy and connectivity criteria are then
subjected to a least-squares minimization against the set of experimental 2Q
curves. This approach was successfully
demonstrated for two test cases in which
X-ray data were available. 29Si ssNMR
spectroscopy on zeolites can be performed under more favorable conditions than spectroscopic studies on other
nuclei, for example, with enhanced
spectral dispersion and the absence of
a strongly coupled proton environment.
It seems likely that adaptations of this
method to other inorganic materials or
isotopically enriched organic molecules
are possible.
Understanding macromolecular organization also is of key relevance in the
context of amyloid fibrils. These selfassembled molecular aggregates are
formed by peptides and proteins with
diverse amino acid sequences, and they
are involved in protein misfolding dis-
Figure 2. a) Complementary use of 29Si double-quantum ssNMR spectroscopy and X-ray powder diffraction (XRD) data to solve structural models
of zeolite frameworks.[10] Letters A–D refer to resonances that are detectable by the ssNMR experiment. b) Combination of high-resolution solidstate NMR spectroscopy and electron microscopy as described by Tycko et al.[12] These studies not only yielded a correlation between distinct fibril
morphologies and molecular structures but may also have important implications in understanding the relationship between fibril structure and
neurotoxicity. The figure was assembled using files kindly provided by M. H. Levitt (a) and R. Tycko (b).
Angew. Chem. Int. Ed. 2006, 45, 1186 – 1188
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
1187
Highlights
orders including Alzheimer@s and Parkinson@s diseases. Images obtained by
transmission
electron
microscopy
(TEM) and atomic force microscopy
(AFM) have revealed that amyloid
fibrils can exhibit multiple distinct morphologies. Are these morphologies related to different molecular structures?
What about the relationship between
molecular structure and biological activity?
High-resolution solid-state NMR
was recently used to answer these questions in the case of the 40-residue bamyloid peptide associated with Alzheimer@s disease, Ab1–40. Firstly, Petkova
et al.[12] prepared residue-specific labeled fibrils by two different growth
conditions—so-called quiescent and agitated parent fibrils. These compounds
were used as seeds to obtain daughter
and granddaughter fibrils under comparable experimental conditions. TEM
images of negatively stained Ab1–40 fibrils revealed that only for quiescent
fibrils can the predominant morphology
be described by a periodic twist and that
the morphological difference is preserved in daughter and granddaughter
fibrils.
To monitor molecular structure, a
series of 2D high-resolution 13C ssNMR
spectra of parent, daughter, and granddaughter fibrils with uniform labeling of
specific residues were recorded. The
patterns of strong one-bond crosspeaks
in these spectra are determined by
isotropic 13C chemical shifts that report
on local structural and conformational
environment. Remarkably, the 2D spectra of quiescent and agitated parent
fibrils showed pronounced differences
in crosspeak patterns (indicated in Figure 2 b by circles) that are transmitted to
the daughter and granddaughter fibrils.
Additional ssNMR data indeed confirmed that different fibril morphologies
have different underlying molecular
conformation and supramolecular organization. Such molecular-level polymorphism and the correlation between
molecular structure and fibril morphology has also been detected for other
protein aggregates involved in neurodegenerative diseases.[13]
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Both studies discussed here hence
underline the complementary use of
imaging, diffraction methods, and solidstate NMR techniques to study molecular complexes. Such information may
not only help to optimize materialscience applications, for example, in
the context of self-assembled nanomaterials with novel electronic or optical
properties, but also offers novel biological insight: In the case of Ab1–40, different fibril morphologies were shown to
exhibit significantly different toxicities
in neuronal cell cultures. Further evidence that biological activity may be
closely related to the details of the fibril
structure comes from a recent structural
study on the HET-s prion protein.[14, 15]
Again, solid-state NMR spectroscopy
provided crucial insights into the structure of prion protein aggregates. Mutations within the central b-sheet regions
of these fibrils that were determined by
high-resolution solid-state NMR spectroscopy seem to correlate with prion
infectivity.[15] These examples demonstrate the growing potential of this
method to provide an important link
between microscopic and crystallographic imaging and molecular functionality.
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