β-Amyloid, Sub-terahertz Microwaves and the Magic Angle

This presentation will selectively cover three closely related sets of experiments that employ magic angle spinning (MAS) NMR, dynamic nuclear polarization (DNP), and their application to structural determination of Ab_1-42 amyloid fibrils.
Approximately 110 years ago, Auguste Deter, the first patient diagnosed with Alzheimer’s disease (AD), passed away and fibrils composed of the Ab_1-42 protein, the toxic species in AD,  were found postmortem in her brain.  Since that time there have been numerous attempts to understand the structure of these fibrils with the goal of hastening a cure.  However, since these species do not diffract to high resolution and are insoluble, a true atomic resolution structure has been lacking. Accordingly, we have developed a suite of MAS dipolar recoupling experiments that permit the measurement of multiple ¹³C-¹³C and ¹³C-¹⁵N distances and the determination of atomic resolution structures of fibrils. We demonstrate the methodology with a description of the high resolution structure of fibrils of monomorphic Ab_1-42, constrained by measurement of over 500 inter- and intramolecular distances.
Second, in order to increase the signal-to-noise in MAS spectra and to better determine molecular structures, we developed methods to perform high field dynamic nuclear polarization (DNP) experiments. The experiments utilize sub-terahertz microwaves (~150-600 GHz) generated by gyrotron microwave sources together with paramagnetic polarizing agents to enhance the sensitivity of MAS NMR experiments. Specifically, we irradiate electron-nuclear transitions that transfer the large electron polarization to nuclear spins via the Overhauser, cross and solid effects. In addition, we have recently initiated time domain DNP in order to circumvent the field dependence of CW DNP. We show that spin locking the electrons and matching the NOVEL condition serves as an effective approach to time domain DNP. Furthermore, the spin locking microwave field can be amplitude and frequency modulated to increase the efficiency of the polarization transfer.  Applications to Ab_1-42 will be presented.