MR imaging of protein folding in vitro employing Nuclear‐Overhauser‐mediated saturation transfer

Abstract

MR Z-spectroscopy allows enhanced imaging contrast on the basis of saturation transfer between the proton pools of cellular compounds and water, occurring via chemical exchange (chemical exchange saturation transfer, CEST) or dipole-dipole coupling (nuclear Overhauser effect, NOE). In previous studies, signals observed in the aliphatic proton region of Z-spectra have been assigned to NOEs between protons in water molecules and protons at the surface of proteins. We investigated a possible relationship between the signal strength of NOE peaks in Z-spectra obtained at B0 = 7 T and protein structure. Here, we report a correlation of NOE-mediated saturation transfer with the structural state of bovine serum albumin (BSA), which was monitored by fluorescence spectroscopy. Encouraged by CEST signal changes observed in tumor tissue, our observation also points to a possible contrast mechanism for MRI sensitive to the structural integrity of proteins in cells. Therefore, protein folding should be considered as an additional property affecting saturation transfer between water and proteins, in combination with the microenvironment and physiological quantities, such as metabolite concentration, temperature and pH.

Nuclear Overhauser Enhancement Mediated Chemical Exchange Saturation Transfer Imaging at 7 Tesla in Glioblastoma Patients

“…This is in agreement with previously published studies [14], [15]. However, the cause of the NOE drop within tumor tissue is still under discussion.…”

“…In the current study we chose 3.3 ppm to reduce APT effects in the asymmetry analysis. Furthermore, we used a saturation field amplitude of 0.7 µT where NOE effects are much stronger than APT effects that peak at 2.1 µT [13], [15]. These theoretical considerations were confirmed in our spectral analysis since we could identify a clear decrease of effects at −3.3 ppm in all tumor parts compared to CLNAWM, while only small background effects at +3.3 ppm most probably due to exchanging amide protons could be detected.…”

Diagnostic performance between contrast enhancement, proton MR spectroscopy, and amide proton transfer imaging in patients with brain tumors

“…First, despite several researches including the current study, the origin of APT signal still remains unclear. Many researchers have demonstrated some biological signature such as cytosolic protein including folding status or amount of specific protein contributes APT signal . Furthermore, there are some discussions about the confounding effects of asymmetry of the solid‐phase MT effect and possible intra‐ and intermolecular nuclear Overhauser effects (NOE) of aliphatic protons and the T 1 value of the tissue to the APT‐weighted image .…”

Advanced MR Imaging in Neuro-oncology

“…tions of intra-and extracellular metabolites to free water molecules which leads to a measurable change in the water signal. With CEST pH-value as well as protein-folding states could potentially be measured in the tumour [50]. The effects however overlap and corrected calculations are necessary in order to draw valid conclusions [49].…”