An H/F/X/Y Fast-MAS NMR Probe Particularly for Alzheimer’s and Cancer Research Abstract More than 20% of current drugs (and a much greater fraction of those in development) are fluorinated (including such block-busters as Prozac, Lipitor, and Ciprobay). Steady progress over the past decade has shown magic angle spinning (MAS) solid-state NMR (ssNMR) to be arguably the most powerful analytical tool for studying macro-molecular structures and their dynamics. For solution NMR, four-channel multinuclear 1H/19F/X/2H probes have recently become more readily available, and such have proven to be extremely valuable for identification and characterization (using 1H/15N, 19F/13C, and 19F/2H/15N methods) of active fragments, their binding to soluble proteins, and their effects on such protein-protein interactions. The problem is that such methods don’t work with insoluble proteins – such as the aggregates and fibrils that are central to Alzheimer’s Disease (AD), Parkinson’s Disease (PD), and probably even prion-mediated diseases. The amyloid beta (Aβ) cascade hypothesis is beginning to bring unity to the field of neurodegenerative diseases, but a key tool for understanding aggregate progression and treatment beyond the stages of the initial seeds has not been available. MAS probes suitable for the needed multi-channel studies of fluorinated drugs and their interactions have not been available for high-field NMR instruments because of the difficulties of prior rf circuits in handling close resonances at high frequencies. During the Phase-I, we demonstrated that a novel single-coil circuit permits, for the first time, efficient high-field H/F/X/Y MAS, with NMR data at 500 MHz and bench experiments and full-wave detailed modeling at 800 MHz. This Phase-II proposal seeks funding to continue the development and testing of high-field H/F/X/Y fast-MAS probes based on a novel “single-coil” rf circuit optimized for 19F detection with simultaneous irradiation or detection on any or all of the other channels, and suitable for MAS at fields from 7-28 T, with rotor diameters from 0.7-3 mm. Analysis suggests that a substantial portion of the spectral line broadening seen in many MAS experiments is from J-couplings (which is not averaged by MAS) to heteronuclei and spinner- dependent effects – thermal gradients, axial vibration, and magnetism. The ability to simultaneously decouple 1H, 2H, and 13C or 15N during 19F detection with fast-MAS in a spinner optimized for high resolution with a circuit and probe design compatible with B0 up to 1200 MHz will permit a dramatic increase in spectral resolution and sensitivity on, for example, 19F-labeled ligands in amyloid assemblies and their precursor aggregates, or in 19F labeled DNA-carcinogen adducts. The novel probe would allow the powerful suite of NMR acquisition and automated structure determination protocols developed for solution NMR, which rely mostly on indirect-detected triple- and quad- resonance schemes, to be su...