"Determination of the atomic structure of large and complex macromolecules, indispensable for the understanding of the mechanisms of biological processes, is one of the most difficult problems in molecular biology. Examples of such structures include subcellular entities, giant protein and nucleic acid assemblies, molecular machines, fibrils, membrane proteins, as well as enveloped viruses and small bacteria. The standard tools for delivering structures at atomic resolution, X-ray crystallography and NMR spectroscopy, are overwhelmed by the complexity of such large assemblies, while cryo-electron microscopy, the highest resolution 3D microscopy used by structural biologists, is hindered by heterogeneity and moreover suffers from radiation damage and low contrast.In this project we propose to develop and apply high-resolution MRI for the direct 3D imaging of macromolecules, comparable to electron microscopy in resolution, but without the need for averaging or staining, and with the unique contrast modalities well-known from clinical applications. Our approach is based on magnetic resonance force microscopy (MRFM), a scanning-probe variety of MRI that has recently enabled 3D imaging of individual virus particles at a spatial resolution of about 5 nm. Our effort will focus on two areas: In a first part we will lay the conceptual and instrumental groundwork needed to make this new technology applicable to biomolecules, including an improvement of the resolution to 1 nm, selective image contrast by stable-isotope labeling, and image reconstruction. In a second part we will apply MRFM to investigate four model systems carefully selected for their structural and biological relevance, including two Amyloid fibrils, a heat-shock protein, and modified virus capsids. The experiments are set to demonstrate the future potential of MRFM for elucidating the large number of disordered and heterogeneous complexes inaccessible to more established structure determination methods."