Structure elements can be predicted using the contact volume among protein residues.

Previously, the structure elements of dihydrofolate reductase (DHFR) were determined using comprehen-sive Ala-insertion mutation analysis, which is assumed to be a kind of protein "building blocks." It is hypo-thesized that our comprehension of the structure elements could lead to understanding how an amino acid sequence dictates its tertiary structure. However, the comprehensive Ala-insertion mutation analysis is a time- and cost-consuming process and only a set of the DHFR structure elements have been reported so far. Therefore, developing a computational method to predict structure elements is an urgent necessity. We focused on intramolecular residue-residue contacts to predict the structure elements. We introduced a simple and effective parameter: the overlapped contact volume (CV) among the residues and calculated the CV along the DHFR sequence using the crystal structure. Our results indicate that the CV profile can recapitulate its precipitate ratio profile, which was used to define the structure elements in the Ala-insertion mutation analysis. The CV profile allowed us to predict structure elements like the experimentally determined structure elements. The strong correlation between the CV and precipitate ratio profiles indicates the importance of the intramolecular residue-residue contact in maintaining the tertiary structure. Additionally, the CVs between the structure elements are considerably more than those between a structure element and a linker or two linkers, indicating that the structure elements play a funda-mental role in increasing the intramolecular adhesion. Thus, we propose that the structure elements can be considered a type of "building blocks" that maintain and dictate the tertiary structures of proteins.