Searching for three-dimensional secondary structural patterns in proteins with ProSMoS

Motivation: Many evolutionarily distant, but functionally meaningful links between proteins come to light through comparison of spatial structures. Most programs that assess structural similarity compare two proteins to each other and find regions in common between them. Structural classification experts look for a particular structural motif instead. Programs base similarity scores on superposition or closeness of either Cartesian coordinates or inter-residue contacts. Experts pay more attention to the general orientation of the main chain and mutual spatial arrangement of secondary structural elements. There is a need for a computational tool to find proteins with the same secondary structures, topological connections and spatial architecture, regardless of subtle differences in 3D coordinates. Results: We developed ProSMoS - A Protein Structure Motif Search program that emulates an expert. Starting from a spatial structure, the program uses previously delineated secondary structural elements. A meta-matrix of interactions between the elements parallel or antiparallel) minding handedness of connections (left or right) and other features (e.g. element lengths and hydrogen bonds) is constructed prior to or during the searches. All structures are reduced to such meta-matrices that contain just enough information to define a protein fold, but this definition remains very general and deviations in 3D coordinates are tolerated. User supplies a metamatrix for a structural motif of interest, and ProSMoS finds all proteins in the protein data bank (PDB) that match the meta-matrix. ProSMoS performance is compared to other programs and is illustrated on a β-Grasp motif. A brief analysis of all β-Graspcontaining proteins is presented.