October 17, 2016

Atomic-scale MRI based on atom sized quantum qubits sensors for individual biomolecules

Researchers at the University of Melbourne have developed a way to radically miniaturize a Magnetic Resonance Imaging (MRI) machine using atomic-scale quantum computer technology.

Capable of imaging the structure of a single bio-molecule, the new system would overcome significant technological challenges and provide an important new tool for biotechnology and drug discovery.

The team propose the use of atomic-sized quantum bits (qubits) normally associated with the development of quantum computers, but here would be employed as highly sensitive quantum sensors to image the individual atoms in a bio-molecule.

"Determining the structure of bio-molecules such as proteins can often be a barrier to the development of novel drugs," said Prof. Lloyd Hollenberg, Thomas Baker Chair in Physical Biosciences at the University of Melbourne.

"By using quantum sensing to image individual atoms in a bio-molecule, we hope to overcome several issues in conventional biomolecule imaging, " Prof Hollenberg said.


Overview of single-molecule MRI using a quantum spin probe. a) The set-up consists of a controllable electronic probe situated 2–4 nm below the surface of the substrate, above which a molecule is positioned. The probe acts as both sensor and gradient field source for the spatial-frequency encoding of the nuclear spins in the target molecule. The equipotential slices (frequency, ωS) of the probe’s coupling field gradient have a characteristic dipole–dipole lobe shape, and can be spatially rotated by varying the direction (θB0, ϕB0) of the background magnetic field B0 (magnitude of order 1-2 T). (b) Initially, the NMR spectrum of the molecule is broadened by the numerous nuclear dipole–dipole interactions (blue lines). The protocol decouples nuclei from each other in the presence of the coupling gradient field of the probe, and resonant excitation of target spins at ωS provides a spatial MRI signal encoded on the probe state. In the spectrum obtained by sweeping the excitation frequency, the peak amplitudes characterize the spin density over the corresponding probe coupling slice. (c) High-level schematic of the interleaved control protocol structure consisting of a spin-echo sequence on the probe spin, and the slice-selective controlled nuclear spin rotation (excitation) embedded into a nuclear decoupling sequence. (d)The target molecule’s nuclear density is sampled for multiple orientations of the interaction slices, followed by transformation from dipolar-slice space to cartesian space, to produce a 3D nuclear spin density image of 1H atoms, or other non-zero nuclear spin species such as 13C. Atomic positions are directly extracted from the density image data.



Detailed outline of the proposed control protocol.

Nature Communications - A quantum spin-probe molecular microscope



State-of-the-art techniques create a crystal of the molecule to be studied and use X-ray diffraction to determine the molecules' average structure. However, the crystalisation and averaging processes may lead to important information being lost. Also, not all bio-molecules can be crystalised - particularly proteins associated with cell membranes, which are critical in the development of new drugs.

"Our system is specifically designed to use a quantum bit as a nano-MRI machine to image the structure of a single protein molecule in their native hydrated environments," added Prof Hollenberg.

"As part of our research in quantum computing we have also been working on the nearer-term applications of atomic-based quantum technology investigating the use of a single quantum bit as a highly sensitive magnetic field sensor," says Prof. Hollenberg.

Atomic qubits can be made to exist in two states at the same time, a disturbingly strange property that not only underpins the power of a quantum computer, but also the sensitivity of qubits as nano-sensors.

"In a conventional MRI machine large magnets set up a field gradient in all three directions to create 3D images; in our system we use the natural magnetic properties of a single atomic qubit," says University of Melbourne PhD researcher Mr. Viktor Perunicic, who was the lead author on the paper.

"The system would be fabricated on-chip, and by carefully controlling the quantum state of the qubit probe as it interacts with the atoms in the target molecule, we can extract information about the positions of atoms by periodically measuring the qubit probe and thus create an image of the molecule's structure." says Mr. Peruncic.

"The system could be constructed and tested relatively quickly using diamond-based qubits. However, to capture really high resolution molecular images in the longer term, CQC2T's silicon-based qubits might have the advantage because they have very long quantum coherence," said Prof. Hollenberg.

"The construction of such a quantum MRI machine for single molecule microscopy could revolutionize how we view biological processes at the molecular level, and could lead to the development of new biotechnology and a range of clinical applications."

Conclusion

They have introduced a new concept for a nano-MRI molecular microscope system based on a generic quantum spin probe, and showed by direct quantum simulation that it allows for the determination of single-molecule structure to high resolution. In this approach, the quantum probe acts as both MRI sensor and gradient field, encoding the target’s real-space spin density in frequency space. The key to the system is a carefully designed protocol interleaving nuclear spin decoupling and phase accumulation on the probe. By systematically performing measurements on the quantum probe over many positions and orientations of the probe-target interaction slices, the probe acquires information about the nuclear spin density in the target molecule. After the deconvolution procedure the nuclear spin density can be mapped out and the atomic coordinates determined. The technique was tested on a non-trivial example—the rapamycin molecule—using a rudimentary sampling procedure and quantum probe coherence parameters already achieved experimentally for phosphorus spin qubits in silicon.

The resolution and average structural errors were found to be at the angstrom level and below. Further improvements and optimization are expected to greatly reduce the overall acquisition time which here should be considered as an upper limit. The protocol length, frequency steps and fine driving field can be refined through a nonlinear rate of change of the probe interaction field, leading to more efficient molecular imaging with uniform resolution through the sampled volume. Our imaging method is suitable for molecules considerably larger than the presented example. Targets of over 20 kDa would benefit significantly from adaptive sampling, that is, starting from a fast low resolution density estimate and iteratively modifying the sampling parameters together with orientation of the interaction slices. For aggregate protein structures of significant spatial extent (10 s of nanometers), an addition of an external classical gradient field (for example, a magnetic tip) could provide a pathway to remote spatio-frequency encoding.

However, more work needs to be done to demonstrate the level of decoupling achievable in the classical gradient fields, experimental timescales required to detect variations of the nuclear spin density at such distances, and the additional influence of the gradient on the quantization axis of both the target and probe spins. The use of more effective decoupling pulses could also have significant impact on the efficiently of the total detection protocol. The protocol was presented for the case of a general spin probe, however, the experimental parameters considered are consistent with current coherence measurements of phosphorus qubits in silicon (Si:P). In the case of the NV spin one could implement a pulsed background field, or attach the molecular sample to an AFM tip scanned through the static field, to avoid off-axis contrast loss, in addition to engineering both appropriate surface and isotopic properties of diamond required to achieve higher electron spin coherence times.

The detection protocol outlined here utilizes only a single electronic spin and, as such, it is limited by the transverse coherence time of the probe T2p. An additional storage qubit, such as the nuclear spin available in both NV and Si:P implementations, can be utilised during the control rotation phase by swapping signal information on the electron spin to the nuclear spin to significantly extend the detection limit to the probe’s longitudinal T1p coherence time. With straightforward sample preparation of molecular targets in their in situ environments, for example, hydrated and coupled protein-drug systems, and hybrid options for adding extra sources of gradient fields (for example, by site-directed spin labelling) to scale up to larger biomolecules, quantum probe-based MRI has significant potential for true single-molecule microscopy.

Abstract

Imaging the atomic structure of a single biomolecule is an important challenge in the physical biosciences. Whilst existing techniques all rely on averaging over large ensembles of molecules, the single-molecule realm remains unsolved. Here we present a protocol for 3D magnetic resonance imaging of a single molecule using a quantum spin probe acting simultaneously as the magnetic resonance sensor and source of magnetic field gradient. Signals corresponding to specific regions of the molecule’s nuclear spin density are encoded on the quantum state of the probe, which is used to produce a 3D image of the molecular structure. Quantum simulations of the protocol applied to the rapamycin molecule (C51H79NO13) show that the hydrogen and carbon substructure can be imaged at the angstrom level using current spin-probe technology. With prospects for scaling to large molecules and/or fast dynamic conformation mapping using spin labels, this method provides a realistic pathway for single-molecule microscopy.

SOURCES- University of Melbourne, Nature Communications

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