This proposal is a competing continuation to """"""""Imaging of Molecules by Oscillator-Coupled Resonance,"""""""" (R01-RR08820), which is presently funded by the Biomedical Research Technology Area of the National Center for Research Resources. The broad objective of the proposed research is to enable biomedical researchers to routinely, quickly, and easily obtain images showing the full three-dimensional structure of the molecules they are studying, in situ, with all their ligands, cross-links, and glycosylation in place. The technical means by which it is proposed to achieve this goal is called magnetic resonance force microscopy. Magnetic resonance force microscopy combines the atomic-scale resolution of scanning probe microscopy with the three-dimensional, nondestructive imaging capacity of magnetic resonance. The proposed research will design, fabricate, and operate prototype magnetic resonance force microscope instruments that achieve sensitivity sufficient in principle to image individual electron moments in spin- labeled biological molecules, in situ, in three dimensions, nondestructively, at cryogenic temperatures, with Angstrom-scale resolution. To the extent that a prototype falls short of achieving the goal of single-spin imaging, the proposed research will identify specific technical obstructions which stand in the way of achieving this goal, characterize these obstructions both theoretically and experimentally, and (if feasible) overcome them. if successful, the proposed research will enable investigators to image three-dimensional biological structures, in situ, with atomic resolution, with the same ease and comprehensive power with which they presently determine gene and protein sequences. This will substantially accelerate the development of effective treatments for presently intractable disorders.
