Protein Functional Surfaces: Global Shape Matching and Local Spatial Alignments of Ligand Binding Sites

We describe a methodology that attempts to optimize two components, global shape and local physicochemical texture, for evaluating the similarity between a pair of surfaces. Surface shape similarity is assessed using a three-dimensional object recognition algorithm and physicochemical texture similarity is assessed through a spatial alignment of conserved residues between the surfaces. The comparisons are used in tandem to efficiently search the Global Protein Surface Survey (GPSS), a library of annotated surfaces derived from structures in the PDB, for studying evolutionary relationships and uncovering novel similarities between proteins.We provide an assessment of our method using library retrieval experiments for identifying functionally homologous surfaces binding different ligands, functionally diverse surfaces binding the same ligand, and binding surfaces of ubiquitous and conformationally flexible ligands. Results using surface similarity to predict function for proteins of unknown function are reported. Additionally, an automated analysis of the ATP binding surface landscape is presented to provide insight into the correlation between surface similarity and function for structures in the PDB and for the subset of protein kinases.It has become apparent that surfaces, comprised of a fraction of the total residues, are the most conserved functional features of proteins. Proteins utilize common surface motifs to create precise chemical environments designed to perform specific functions. These motifs are not restricted to a single protein scaffold but can be found within different protein folds or at domain/domain and subunits interfaces. While biochemical activity can be attributed to a few key residues (e.g catalytic triads), the broader surrounding environment (i.e. auxiliary residues in spatial proximity) often plays an equally import role in fine-tuning molecular recognition and/or catalysis.Powerful evolutionary forces have allowed proteins to govern ligan