Research Themes

Find out about the areas of research we investigate.

Our capabilities

Atomic nuclei have a mass and an electric charge. In addition, some types of nuclei also carry a magnetic moment. They therefore act like tiny bar magnets, each with a south and a north pole. As it turns out, this property offers a unique window into the inner workings of atoms, molecules, liquids and solids, and even living organisms.

When magnetic atomic nuclei are placed in a strong magnetic field, their magnetic moments rotate (precess) around the field, allowing them to absorb and emit radio waves. Governed by the laws of quantum mechanics, this precession happens at a very precisely defined frequency, and produces electromagnetic signals that can be detected with great accuracy.

By carefully examining these signals, a wealth of information about the molecules surrounding the atomic nuclei can be obtained, revealing their structure, chemical reaction mechanisms, and dynamics. This forms the basis not only of nuclear magnetic resonance spectroscopy, but also of magnetic resonance imaging (MRI), which is of paramount importance in medical diagnostics.

Our research aims to extend the possibilities of magnetic resonance and includes exploring methods that allow to align the nuclear spins in a sample all in the same direction at the start of a measurement, thus dramatically enhancing the magnetic resonance signal.

We are pioneers in the development of methodology and technology to access special quantum states with unusually long lifetimes and in exploiting those in the study of diffusion in porous media among several other applications. Advanced multi-dimensional spectroscopy allows us to study the structure of proteins that are crucial for the human immune system. We are developing magnetic resonance methods to study exotic materials such as superconductors and fullerenes. Integrating NMR spectroscopy with tissue cultured on 3D-printed scaffoldings, could support the development of new drugs while reducing the need for animal experiments. Solid-state NMR studies allow to optimise catalysts, thereby increasing the yield of chemical production processes.

Our research is:

Highly Interdisciplinary
Our interests span from theoretical spin dynamics to biological NMR going through solid-state NMR, hyperpolarised NMR, Cryogenic NMR, long-lived spin states, diffusion and flow NMR, microfluidics NMR. As such we work at the borderlines of chemistry, biology, physics, medicine, and engineering.
Frontline
We conduct excellence in frontline NMR research. The Magnetic Resonance group is investigating on a number of frontline NMR topics and is recognised among the world leaders in the field. This is demonstrated by the number of national and international prizes we were awarded (see our individual profile page), peer-reviewed papers and books we authored, and the frequent invitations to speak at major conferences, NMR schools and other events.
Well-funded
Over the last 10 years we have raised >£30M in research funds from UKRI, EU and several different Trusts. Beyond these core projects, we are involved in a wide range of collaborations, typically contributing NMR know-how to assist research in materials science, organic chemistry, and other fields.

Biological Nuclear magnetic resonance (NMR)

Biomolecular NMR spectroscopy is a highly versatile and powerful technique for the analysis of biological systems. It provides unique and valuable insights into the atomic structure and dynamics of biomolecules and their interactions. Furthermore, NMR allows the analysis of biological pathways with applications to environmental sciences and medicine.

Overview

The complex molecular composition of biological systems and their finely tuned interactions are integral for their function. These heterogeneous systems contain both soluble biomolecules, such as those found in the cytoplasm and extracellular milieu and insoluble species such as integral membrane proteins and protein fibres. Accordingly, we employ a combination of both solution and solid-state NMR methodologies to probe the molecular structure, dynamics and interactions of constituent biomolecules and their modulation by complex environments.

Currently our research addresses several key biological questions including antigen processing and membrane transport, cellular signal transduction and membrane remodelling. Furthermore, the synergy that exists between solution and solid-state NMR is also providing us with a valuable opportunity to study the disease processes that lead to the formation of insoluble protein deposits such as those associated with conditions such as Alzheimer’s and Parkinson Disease.

The scope for NMR in the analysis of biological samples extends beyond the realms of the structural and dynamic characterisation of biomolecules. A number of our studies are now focussed on the analysis of biological samples to study metabolite levels and the transport of these metabolites and other small molecules across the cell membrane. These studies are providing a wealth of information from understanding how corals respond to changes in climate to the development of novel chemistries to enhance the efficacy of new drugs.

Our efforts in this area are focused on: 

To understand how antigens are processed and presented to the immune systems, with implications for our understanding of cancer and autoimmune disease.
The processes that lead to the aberrant folding of proteins that are associated with amyloid diseases including Alzheimer’s and Parkinson’s Disease.
How integral membrane proteins interact with drugs, signalling molecules and lipids in the cell membrane to influence the activity of ion channels and receptors.
The partitioning and transport of drugs and small molecules across cellular membranes.
Membrane remodelling and its role in micro-vesicle formation and viral replication.
The enzymatic processing of antigenic peptides
The molecular response to heat adaptation in corals

You can read more about our research in the field of Structural Biology here.

Staff

Joern Werner Reader in Structural Biology

Phil Williamson Associate Professor

Cryogenic NMR

Many interesting physical phenomena occur at very low temperatures, such as quantum rotation and superconductivity. NMR at cryogenic temperatures allows us to study them.

Overview

The NMR signal originates from the interaction between a time-dependent magnetic field and nuclei with non-vanishing nuclear spin. NMR can be used to study molecular structure and dynamics with atomic resolution. Molecular motions are temperature dependent. By lowering the temperature, some motions are slowed down or even frozen, but many interesting motions involving light-weight molecules or molecular fragments, like CH3 groups, water molecules and hydrogen, persist even at very low temperature. These motions are very unhindered and fast, and they are often poorly described by classical physics. This makes it difficult to understand them in details at room temperature.

Solid state NMR spectra for static samples are often very broad and uninformative. Sample rotation (magic-angle spinning, MAS) provides resolution of unequivalent chemical sites, narrower and more intense signals. The MAS technique has been one of the major advances of the last 50 years and has contributed to the widespread of solid state NMR. Low temperature MAS NMR (cryoMAS) will broaden the range of potential NMR applications even further, due to a signal gain and to the capability to use much smaller samples. To date, most NMR studies at very low temperature have been performed on static samples due to technical limitations. The target of many of these studies are physical phenomena that typically occur only at low temperature. Important information are difficult to extract from static experiments on complicated molecular systems, due to both the lack of resolution and the averaging of some properties, with a loss of insight into the local molecular environments and the dynamics.

To date, there are only few examples in the world of instrumentation for MAS NMR at very low temperature (cryoMAS). In UK, a cryoMAS system is being developed uniquely at the University of Southampton. CryoMAS will open roads towards studies of many fundamental physical phenomena with details not available with other techniques. Our research interests focus on the physics of non classical, low temperature motions and their impact on NMR, using cryoMAS.

Our efforts in this area are focused on: 

developing new hardware to perform static and magic-angle-spinning experiments at cryogenic temperatures
exploiting the technique to study spin isomerism, spin isomer conversion and quantised molecular motion in molecular endofullerenes
exploiting the technique to study novel superconducting materials below their Curie temperature
exploiting the technique as a way to enhance sensitivity in NMR studies of biosolids and proteins

Staff

Marina Carravetta Associate Professor
Malcolm Levitt Professor of Physical Chemistry

Hyperpolarised NMR

The enormous signal enhancement achieved through hyperpolarisation techniques is currently revolutionising the range of NMR, extending the method into new areas such as in vivo characterisation of cancer metabolism in humans and the NMR of thin surface layers.

Overview

Hyperpolarisation techniques enormously increase the signal strength of NMR experiments, with enhancements exceeding 4 orders of magnitude demonstrated experimentally. The available hyperpolarisation techniques include spin-exchange optical pumping (restricted to noble gases such as ¹²⁹Xe), parahydrogen-induced polarisation (PHIP), its variant signal amplification by reversible exchange (SABRE) and dissolution-dynamic nuclear polarisation (dDNP). In our laboratory we are working on dDNP and PHIP.

The PHIP method consists in preparing para-enhanced hydrogen gas by deposition of hydrogen on a cold (typically <77K) paramagnetic surface (charcoal, Fe₂O₃ or similar) and then reacting this with an unsaturated bond present in the molecule of interest. The addition reaction transfers the hyperpolarised (singlet) order from para-H₂to the molecule of interest which can now produce enhanced NMR signals.

The dDNP method transfers the very high thermal polarisation of electrons at low temperatures (~100% at 1.5K) to nuclear spins by applying microwaves. A molecular substrate is mixed with a substance containing unpaired electrons and cooled to about 1.5K. The sample is irradiated with microwaves in the presence of a magnetic field to establish the nuclear polarisation and then rapidly dissolved by a stream of hot solvent. This produces a solution with a high degree of hyperpolarised Zeeman order as well as some hyperpolarised singlet order. Most substances may be hyperpolarised this way, unless they do not tolerate the extreme conditions.

The availability of general-purpose hyperpolarisation methods such as dDNP have revolutionary impact. Some experiments that were considered to be impossible, such as the metabolic imaging of human cancer by MRI, have now been demonstrated in a clinical context. Nevertheless all such applications still remain on the borderline of feasibility. For example the spatial resolution of hyperpolarised MRI imaging of cancer metabolism is strongly compromised by the loss of signal during transport and purification of the hyperpolarised material. Improvements to hyperpolarisation protocols and the ability to transport hyperpolarised material would improve the emerging techniques and open up new areas.

Our efforts in this area are focused on: 

building a 188 GHz nuclear spin polariser for dissolution-DNP
developing new methodology for the dissolution of hyperpolarised samples
investigating the phenomenon of quantum-rotor-induced polarisation
developing a device that uses parahydrogen-enhanced polarization (PHIP) to generate a continuous flow of hyperpolarized material for practical applications
developing pulse sequence for the efficient conversion of hyperpolarised singlet order (generated via PHIP) into hyperpolarised magnetisation
combining hyperpolarisation techniques with long-lived spin states to obtain long-lived reservoirs of hyperpolarisation
combining dissolution-DNP with supercritical fluids for storage and transport of hyperpolarised spin order

Staff

Malcolm Levitt Professor of Physical Chemistry
Giuseppe Pileio Associate Professor in Nuclear Magnetic Resonance, Director of PGT Programmes

Long-lived nuclear spin states

The ability to preserve spin polarisation for several minutes or hours opens many new possibilities in NMR and MRI, from enhancing NMR studies of translational dynamics up to tracing and imaging of molecular tags in materials or in-vivo.

Overview

NMR experiments exploit modes of nuclear spin order which represent particular configurations of the nuclear spin orientations. Most NMR experiments involve Zeeman order which represents a net orientation of the nuclei along an applied magnetic field. A small amount of Zeeman order is generated through natural thermal processes by allowing the sample to equilibrate in a strong magnetic field. Although the thermal Zeeman order is very small (typically only ~10^-5), all conventional NMR and MRI techniques rely on it. Its small size makes NMR a low sensitivity technique when compared to optical spectroscopy and many other methods. The process by which thermal Zeeman order is established in a magnetic field is called spin-lattice relaxation and typically follows approximately first-order kinetics with a time constant denoted T₁. In a typical solution, T₁ ranges from tens of milliseconds (water in body tissues) up to a few tens of seconds (selected ¹³C or ¹⁵N-labelled substrates).

In 2004 we demonstrated that coupled clusters of nuclear spins support classes of nuclear spin order (called long-lived states, LLS) which in some circumstances have much longer lifetimes than T₁. One subclass of such states occurs in molecules containing coupled pairs of spins-1/2 and is called singlet order. This may be viewed as a spin configuration in which pairs of magnetic nuclei are oriented in opposite directions such as their net magnetisation cancels out. The decay time constant for singlet order is denoted T_S and may greatly exceed T₁. Values of T_S have been observed which are > 10 min for proton pairs, > 25 min for nitrogen-15 pairs and >1 hour for carbon-13 pairs.

In suitable systems, the two forms of nuclear spin order (Zeeman and Singlet) may be interconverted by using suitable sequences of applied magnetic fields.

This is an highly active research area where our efforts are focused on: 

developing theoretical and experimental tools for handling long-lived nuclear spin states
developing nuclear spin relaxation models to understand and predict the relaxation decay rates of those states
design and synthesis of new molecules supporting long-lived states, in collaboration with synthetic chemists
exploiting long-lived states in the context of chemical reactions and NMR imaging
combining hyperpolarisation techniques (para-H₂ and dissolution-DNP) with long-lived states to prepare long-lived reservoirs of hyperpolarisation
exploiting the use of long-lived states as tags in imaging experiments
exploiting the use of long-lived states to characterise transport phenomena in porous media

Staff

Malcolm Levitt Professor of Physical Chemistry
Giuseppe Pileio Associate Professor in Nuclear Magnetic Resonance

Singlet-Diffusion NMR

Diffusion-NMR is a powerful technique with applications that span from material science to medicine. When combined with long-lived spin states it can provide important translational dynamics information such as tortuosity and compartmentation in macrostructures.

Overview

With the characteristic non-invasiveness and non-harmfulness of Nuclear Magnetic Resonance (NMR), diffusion-NMR techniques can infer information on molecular diffusion in various media. Diffusion-NMR has applications that range from analytical sciences where it can be used, for example, to sort out complex molecular mixtures according to different diffusion coefficients, up to medicine where it is used to obtain contrast between biological tissues based on differences in molecular diffusion.

Porous media, which are ubiquitous in nature, with examples including rocks, bones, wood etc. are perhaps the most suitable systems to be characterised through diffusion-NMR. And indeed, scientific literature contains numerous examples of such investigations. However, because conventional NMR signals last typically for only up to a few seconds, diffusion-NMR studies have some limitations. The measurements of diffusion are done on a microscopic level by registering the changes in the intensity of an NMR signal as molecules diffuse in solution. The longer the diffusion time, the further the molecules diffuse, so that the registered change in signal is more dramatic and the more accurate the measurement. Molecular diffusion is affected by the microscopic structure of the material. Therefore diffusion-NMR is a very sensitive tool to probe micro-structures, hence its great utility in porous media investigations. However, its sensitivity to dimensions is directly linked to the timescale explored i.e. to the available diffusion time. Limitations to diffusion time due to the lifetime of conventional NMR signals therefore restrict the technique to geometries within 100 micrometres. Since many interesting porous structures have pores larger than 100 micrometres the technique cannot probe pore connectivity in those systems hence cannot provide a measure of tortuosity which is of instrumental importance in many areas including oil engineering and battery development.

Long-lived spin states are configurations of nuclear spin states displaying very long lifetimes that can reach in some cases one hour. This lifetime extension can be used in diffusion-NMR to prolong the diffusion time and obtain a better accuracy in diffusion measurement plus the possibility to access information on pore connectivity and hence measure tortuosity.

We are developing methodology that exploit long-lived states to expand the accessible diffusion time in diffusion-NMR experiments thus giving access to measurement of tortuosity, macroscopic compartmentation, and diffusion anisotropy in porous media.

Our efforts in this research area are focusing on: 

developing molecular probes of diffusion that support long-lived states to give access to very long diffusion times
developing NMR methodology to measure diffusion by encoding positional information on long-lived spin states
developing a simulation procedure for simulation of complex NMR experiments in porous systems
measuring tortuosity, anisotropic diffusion and macrostructures in porous media
developing low-field hardware to facilitate these experiments

Staff

Giuseppe Pileio Associate Professor in Nuclear Magnetic Resonance

Solid-state NMR Methodology

Solid-state NMR is a powerful technique that can provide valuable structural and dynamic information at the molecular level, even for systems that lack long-range order and cannot be studied by crystallography. These include many technologically important materials and also important biological systems such as membrane proteins and fibrils.

Overview

We are developing novel solid-state NMR approaches for the characterisation of materials that are unsuitable for techniques such as crystallography. 

Our efforts in these areas are focused on: 

Enhancing sensitivity using cryogenic magic-angle spinning and paramagnetic relaxation agents. These studies seek to identify novel ways to enhance the sensitivity of solid-state NMR using low temperature measurements. Coupled with research into paramagnetic reagents which can enhance the speed with which measurements can be performed, and potentially provide structural information, we aim to realise a significant enhancement in sensitivity.
¹⁴N solid-state NMR of biomolecules. In nature the most abundant isotope of nitrogen is nitrogen-14. Traditionally however, studies of biomolecules by NMR have relied on nitrogen-15 labelling. This precludes the analysis of biological materials where labelling is not available and results in the loss of a wealth of structural and dynamic data which is present in the nitrogen-14 spectrum. We are currently developing a range of techniques that permit the analysis of nitrogen sites within biomolecules, environmental samples and pharmaceuticals where previously labelling would have been viewed as a pre-requisite.
The solid-state NMR of superconducting materials, such as fullerides.
The solid-state NMR of materials exhibiting quantum rotor behaviour at low temperatures, such as small molecule endofullerenes and related systems.

Staff

Marina Carravetta Associate Professor
Malcolm Levitt Professor of Physical Chemistry
Phil Williamson Associate Professor