Confluence of Major NMR Methods and
Instrumentation Advances Enables Next-Generation GHz Technology
with Focus on Structural Biology, Macromolecular Complexes,
Membrane Proteins and Intrinsically Disordered Proteins (IDP)
At the 56th Experimental Nuclear Magnetic Resonance Conference
(www.enc-conference.org), Bruker announced it is launching its
next-generation of GHz-class NMR technology, with a combination of
major method and instrumentation advances, which enable even more
advanced scientific and translational research in structural
biology, drug discovery and the study of macromolecular
complexes.
Actively Shielded Aeon 1 GHz NMR Magnet
(Photo: Business Wire)
The primary focus of Bruker’s unique, next-generation GigaHertz
(GHz) Nuclear Magnetic Resonance (NMR) spectroscopy technology is
to enable breakthrough fundamental research in molecular and cell
biology on Intrinsically Disordered Proteins (IDPs). In particular,
ultra-high field NMR in combination with other experimental and
computational methods, has recently been shown to enable more and
more detailed studies of the structural ensembles;
post-translational modifications; dynamics; multiple interactions;
specific binding partners;signaling and regulatory roles; formation
of membrane-less cellular organelles; and other important functions
of Intrinsically Disordered Proteins (IDPs). Due to the scarcity of
understanding of the molecular functions for the vast majority of
IDPs, they are sometimes also referred to as the ‘Dark Proteome’.
Please note the link to a short video on IDPs below.
The next-generation GHz NMR technology is the result of a
confluence of recent break-through scientific discoveries, major
technical achievements and key, customer-driven new NMR methods
development, including:
- New Actively-Shielded 1 GHz NMR
Magnets
- Novel High-Dimensionality and Fast
Acquisition NMR Methods
- 13C and Novel
15N Direct Detection for Large Proteins and IDPs
- Advanced Parallel NMR with Multiple
Receiver Acquisition
- New 3 mm TCI CryoProbe for GHz-class
Indirect Experiments
- New Triple-Gradient 5mm
CryoProbes
- Novel Single-Story Ascend Aeon 900
MHz Magnets
- New 1 GHz ultra-fast 111 kHz MAS
solid-state NMR probe (see separate press release)
For the scientific community, and scientific press and media, a
Scientific and Technical Section is
provided below.
Frank H. Laukien, Ph.D., President and CEO of Bruker
Corporation, commented: “The study of IDPs is one of the most
important next frontiers in biology and in understanding disease
pathogenesis. We are very excited to usher in the next-generation
of GHz NMR technology. Its primary mission is to enable molecular
and cell biologists to accelerate their quest to illuminate the
‘Dark Proteome’, with expected enormous benefits for healthcare and
patients. The next-generation GHz NMR tools for IDP research are
expected to dramatically accelerate our understanding of many
fundamental biological processes. Moreover, IDP research has
already delivered key discoveries, and offers great promise, for
breakthroughs in the study of cancer biology and neurodegenerative
diseases, such as Alzheimer’s Disease.”
About Bruker Corporation (NASDAQ: BRKR)
For more than 50 years, Bruker has enabled scientists to make
breakthrough discoveries and develop new applications that improve
the quality of human life. Bruker’s high-performance scientific
research instruments and high-value analytical solutions enable
scientists to explore life and materials at molecular, cellular and
microscopic levels.
In close cooperation with our customers, Bruker is enabling
innovation, productivity and customer success in life science
molecular research, in applied and pharma applications, in
microscopy, nano-analysis and industrial applications, as well as
in cell biology, preclinical imaging, clinical research,
microbiology and molecular diagnostics. For more information,
please visit www.bruker.com.
For more information on Bruker at ENC 2015, please visit:
www.bruker.com/enc
For a short, educational video on IDPs, please go to:
www.idpbynmr.eu/home/video.html
Scientific and Technical Section on
Introduction of Next-Generation GHz NMR Technology for IDP Research
at ENC 2015
1. New Actively Shielded 1 GHz NMR
Magnet: A Bruker 1 GHz NMR system with a first-generation,
unshielded 23.5 Tesla magnet has been running very successfully at
the Ultra-High Field NMR Center in Lyon, France since 2009, with
remarkable scientific output.
Bruker intends to deliver the world’s first,
next-generation 1GHz NMR systems with actively-shielded Aeon™ 1 GHz magnets to
the University of Bayreuth, Germany, in late 2015, and to the
University of Toronto, Canada in the first half of 2016. Active
shielding reduces the space volume occupied by the 5 Gauss stray
field of this two-story magnet by more than one order of magnitude,
and makes siting of next-generation Aeon™ 1 GHz magnets
straight-forward.
The new Aeon™ 1 GHz magnets have been
developed using the latest, proprietary, advanced superconductors
from Bruker’s Energy & Supercon Technologies (BEST) division.
The Aeon™ 1 GHz also features proprietary, fully-integrated,
novel, active refrigeration technology, which eliminates the need
for liquid Nitrogen completely, and brings liquid Helium boil-off
essentially to zero in normal operation. Bi-annual pulse-tube
cooler maintenance can be done at full field with minimal
disruption and down-time. By mid-2016, Bruker expects to have
capacity for four to six Aeon™ 1 GHz magnets annually.
2. Novel High-Dimensionality and Fast
Acquisition NMR Methods in TopSpin™ 3.5: Recent years have seen
breakthroughs developed by the NMR research community in APSY
(automated projection spectroscopy) and in fast NMR acquisition
using Non-Uniform Sampling (NUS). These and other seminal
NMR methods, pulse programming and data analysis advances, together
with GHz-class NMR sensitivity and spectral dispersion, are
essential for increasingly automated, sequence-specific backbone
and side chain resonance assignments of larger globular proteins,
and their complexes, from chemical shift correlations determined by
nD (n >= 4) NMR experiments. Fast high-dimensional methods like
NUS, projection spectroscopy and APSY methods are particularly
needed for IDPs, or proteins with long intrinsically disordered
regions (IDRs) due to the inherently lower spectral dispersion of
many IDPs/IDRs.
Bruker’s latest NMR software version
TopSpin™ 3.5 now enables projection spectroscopy, including
APSY-NMR, and routine NUS acquisition, and supports
automatic execution of suitable pulse programs with fast
acquisition techniques, with access to up to 6-dimensional NMR
experiments at significantly reduced acquisition times. NUS
techniques acquire only a subset of the data points of high
dimensionality experiments and use novel reconstruction methods
that ultimately allow the extraction of complete sets of chemical
shift information. One new introduction in the field of
reconstruction of non-uniformly sampled data sets is compressed
sensing (CS) . It provides a general approach for a major
reduction of measuring time and quality improvement of the sparsely
detected spectra.
These recent and now fully integrated NMR
techniques are taking full advantage of the advances in GHz NMR
sensitivity, due to highest magnetic field strengths and new
CryoProbe developments (see below), in cases where the time
required to acquire high-dimensionality data set in conventional
ways would be completely prohibitive. The confluence of major
strides in NMR methodology, software and NMR technology together
have enabled the next-generation level of break-through NMR
performance that is a prerequisite for large-scale functional and
disease-directed exploration of the universe of IDPs/IDRs, which
today remains largely unexplored.
Professor Vladislav Orekhov from the Swedish
NMR Center at the University of Gothenburg said: “I am fascinated
by the rapid progress in the theory and applications of novel
signal acquisition and processing techniques that push boundaries
of the dimensionality and resolution of NMR spectra, and permit
real-time investigation of biological processes with atomic
resolution. A combination of ultra-high field GHz magnets and
non-uniform sampling techniques greatly enhances our capability to
tackle challenging biomedical problems, including the
characterization of large protein machines and intrinsically
disordered proteins. I have no doubts we are witnessing the most
striking development in this field!”
3. 13C and Novel 15N Direct
Detection for Large Proteins and IDPs: Direct 13C
detection of isotopically labelled proteins has become an
essential tool in high-field NMR in recent years, with well-known
advantages for metalloproteins and IDPs, and providing
complementary information to main-stream indirect 1H-detected NMR
experiments in structural biology. The introduction of
next-generation 5mm TXO and 5mm TCI CryoProbes up to
1 GHz, both using cold 15N preamplifiers, in conjunction with the
latest GHz-class magnets, enabled by recent, novel 15N
direct-detect NMR methods, now make direct 15N detection
advantageous, sensitive and quite useful in very large globular
proteins and in IDPs, due to the longer relaxation times, high
resolution and low chemical shift anisotropy of 15N spectra.
Furthermore,15N detection can be beneficial
in cases where carbon-detected methods suffer from multiple
couplings to neighboring carbons, or in the study of proline-rich
protein domains. Another attractive area of 15N detection are
paramagnetic metallo-proteins, where 1H or even 13C magnetization
is broadened beyond detection limits. These 15N detected
experiments are critically dependent on the high sensitivity
delivered by the new 5mm TXO or TCI CryoProbes with
cryogenic 15N preamplifiers, and it turns out that 15N-TROSY
experiments are expected to have their highest sensivitiy benefit
at around 1 GHz proton frequency.
Professor Gerhard Wagner of Harvard Medical
School, a pioneer of 15N direct detection, stated: “Direct 15N and
13C detection methods have recently been evolved and found to be
almost as sensitive as 1H detection techniques, benefitting from
the slow transverse relaxation. This opens new opportunities for
studies of proline-rich polypeptides often found in regulatory
regions, such as phosphorylation domains. However, spectra of such
domains are typically poorly dispersed and highest field strengths
will be needed to reveal mechanisms of phosphorylation-dependent
switch mechanisms. Availability of GHz-class NMR instruments will
be important for revealing mechanisms of phosphorylation-dependent
signaling switches.”
4. Parallel NMR with Multiple Receiver
Acquisition: The unique multiple receiver technology of
Bruker’s AVANCE III HD platform now enables elegant and
efficient polarization sharing and parallel acquisition NMR
spectroscopy to detect simultaneously signals from multiple nuclear
species, such as 1H, 2D, 13C, 15N, 19F and 31P. The multi-receiver
experiments can also be used in combination with the fast
acquisition schemes such as projection-reconstruction techniques
and can provide significantly more information from a single NMR
measurement, compared to the conventional single receiver
techniques. Parallel NMR with multi-receiver acquisition is also
well suited for structure verification or elucidation of small
molecules in drug development and discovery, as well as for higher
dimensionality experiments for studying globular proteins or
IDPs.
Professor Markus Zweckstetter, Group Leader
at the German Center for Neurodegenerative Diseases at the
University of G�ttingen, stated: “We are thrilled by the new
opportunities to use next-generation GHz NMR technology to perform
5-7 dimensional NMR experiments on intrinsically disordered
proteins (IDPs) of high medical relevance, as well as solid-state
NMR experiments on membrane proteins in native-like environments,
or on complexes of IDPs with diagnostic and therapeutic ligands. In
particular, we are excited about further boosting the resolution of
6-dimensional experiments on IDPs with GHz-class NMR spectrometers
with next-generation CryoProbes and parallel NMR capabilities by a
significant factor, compared to traditional high-field NMR
spectrometers. We are convinced that this step-change in
information content on IDP function will help the scientific
community to unravel the ‘Dark Proteome’ of IDPs, and enable
completely new insights into key biological and disease processes,
particularly in cancer and neurodegenerative diseases.”
5. 3 mm TCI CryoProbe for GHz-class
Indirect Experiments: This new design of smaller diameter NMR
CryoProbes is advantageous for highest-field GHz
biomolecular applications, when sample volumes are limited and
sample salt concentrations are in the physiological range. The new
3mm design also delivers shorter radiofrequency (RF) pulses at
equivalent RF power, compared to 5 mm CryoProbes, an
important benefit for IDP dynamics experiments, when working at GHz
fields.
Professor G�ran Karlsson, Director of the
Swedish NMR Center at the University of Gothenburg, was Bruker’s
key collaborator in the development of 3mm CryoProbes. He
commented: “The performance of the new 3 mm TCI CryoProbe on
our 800 MHz is just spectacular. For some time we have been working
with 3mm samples in structural biology, and with the new 800 MHz
3mm CryoProbe we obtain dramatic S/N increase . In
metabolomics applications, we benefit from both, the increase in
S/N and the ability to work with reduced sample volumes. For many
applications in life science research, the 3mm CryoProbe
represents a leap forward. We’re planning to order the 3mm
CryoProbe also for our 900 MHz spectrometer.”
6. Triple-Gradient 5mm CryoProbes: The
latest 5mm TCI CryoProbes can now optionally be equipped
with actively-shielded, triple-axis pulsed field gradient coils.
Triple axis gradients enable faster pulse sequence optimization
with respect to gradient coherence selection. In addition, the
residual water signal is typically reduced by a factor of 2-3
compared to single axis gradient probes. In addition to localized
spectroscopy, recently published fast methods such as SMART
NMR also become accessible.
Professor Lewis Kay at the University of
Toronto, Canada, was Bruker’s key collaborator in the development
of triple-axis gradient CryoProbes. Dr. Kay explained: “We
are eagerly anticipating delivery of triple-axis gradient
CryoProbes for our 600 MHz, 800 MHz and 1 GHz spectrometers. The
ability to significantly improve water suppression by replacing
Z-coherence transfer selection gradients with those along X or Y,
for example, makes optimum pulse sequence development easier.
Better suppression of water will lead to significantly less noise,
especially near the water line, as well as better baselines,
translating into higher quality data sets and subsequent
improvement in signal to noise.”
7. Novel Single-Story Ascend Aeon 900 MHz
Magnet: The world’s first compact, single-story 900 MHz NMR
magnet for high-resolution protein NMR which is being introduced at
ENC 2015, integrates advanced refrigeration technology, and
obviates the need for any cryogen refills. Previous 900 MHz magnets
required two-story laboratories, limiting the wider adoption of
ultra-high field NMR, except in specialized NMR laboratories.
Professor Paul R�sch is the Director of the
Research Center for Bio-Macromolecules at the University of
Bayreuth, Germany, where the installation of the world’s first
Ascend Aeon 900 magnet for high-resolution NMR was recently
completed. Dr. R�sch stated: “Our new Ascend Aeon 900 magnet
enables long-term, helium consumption-free operation without user
maintenance. The reduced height and stray fields of this novel,
compact, ultra-high field magnet, maximize siting flexibility and
thus reduce laboratory space costs. From our perspective both
factors are key requirements to further grow the adoption of
ultra-high field NMR in biology, and also to expand into clinical
research. We’re very pleased with the stability and the performance
of our new Ascend Aeon 900 magnet.”
The University of Bayreuth will also be the
site for the world’s first installation of a shielded 1 GHz magnet,
presently expected in the fourth quarter of 2015.
8. New 1 GHz ultra-fast 111 kHz MAS
solid-state NMR probe: see separate press release
Photos/Multimedia Gallery Available:
http://www.businesswire.com/multimedia/home/20150420005297/en/
Bruker CorporationMedia Contact:Dr. Thorsten Thiel, +49
(721) 5161–6500Director of Marketing
Communicationsthorsten.thiel@bruker.comorInvestor
Contact:Joshua Young, +1 978-663-3660, ext. 1479Vice President,
Investor Relationsjoshua.young@bruker.com
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