Research opportunities are available that focus on the development of precision cryo-electron microscopy (cryo-EM) measurements and analysis tools to enable robust high-resolution (better than 0.3 nm) structural characterization of flexible, protein-based drugs (i.e., protein biopharmaceuticals or biologics) that are below a molecular weight limit of ~ 200 kDa.   To address current limitations of low contrast and the challenges with alignment and averaging of small, flexible biomolecules, we are simultaneously pursuing two strategies for bioengineering sample platforms for cryo-EM measurements.  One approach will be to tag the protein of interest with gold nanoclusters, determine the gold-gold distances, and use this information to perform the alignment.  The other will be to anchor the mAb to a large, well-characterized macromolecular system (e.g., a virus particle) to increase the apparent molecular weight of the analyte.  In each case, we are utilizing the NIST mAb (RM8670) as a model system for the proposed measurements since it has been extensively characterized by multiple analytical, biophysical and structural methods. Both strategies will require the development of new data analysis and mathematical modeling tools to enable quantification of the inherent uncertainty in the various features of the calculated structures.