The present invention provides methods for crystallographic structure determination employing hydrogen exchange analysis. Hydrogen exchange analysis is used to identify unstructured regions of a protein, which are then deleted to obtain one or more modified proteins for crystallization and structure determination. Optionally, an initial hydrogen exchange stability map of a protein is compared to that of at least one modified form of the protein to identify unstructured regions, while retaining characteristic structure of the native protein. Hydrogen exchange analysis is performed by determining the quantity of isotope and/or rate of exchange of peptide amide hydrogen(s) with isotope on a labeled protein. Proteins with fewer unstructured regions, and thus improved hydrogen exchange structural maps, are optimal for high quality crystallization and structure determination.