Exploring the Composition of Protein-Ligand Binding Sites on a Large Scale

Abstract

The residue composition of a ligand binding site determines the interactions available for diffusion-mediated ligand binding, and understanding general composition of these sites is of great importance if we are to gain insight into the functional diversity of the proteome. Many structure-based drug design methods utilize such heuristic information for improving prediction or characterization of ligand-binding sites in proteins of unknown function. The Binding MOAD database if one of the largest curated sets of protein-ligand complexes, and provides a source of diverse, high-quality data for establishing general trends of residue composition from currently available protein structures. We present an analysis of 3,295 non-redundant proteins with 9,114 non-redundant binding sites to identify residues over-represented in binding regions versus the rest of the protein surface. The Binding MOAD database delineates biologically-relevant “valid” ligands from “invalid” small-molecule ligands bound to the protein. Invalids are present in the crystallization medium and serve no known biological function. Contacts are found to differ between these classes of ligands, indicating that residue composition of biologically relevant binding sites is distinct not only from the rest of the protein surface, but also from surface regions capable of opportunistic binding of non-functional small molecules. To confirm these trends, we perform a rigorous analysis of the variation of residue propensity with respect to the size of the dataset and the content bias inherent in structure sets obtained from a large protein structure database. The optimal size of the dataset for establishing general trends of residue propensities, as well as strategies for assessing the significance of such trends, are suggested for future studies of binding-site composition.

Small-molecule binding sites to explore protein–protein interactions in the cancer proteome

“…Identification of binding sites is accomplished by analyzing the three-dimensional structure of a protein. Several computational methods have been developed to scan the surface of proteins for binding sites (18). Binding site detection algorithms, such as CavBase (19), fpocket site (20), and LIGSITE CSC (21), often represent the protein structure through the use of points on a three-dimensional grid.…”

Physics-Based Visual Characterization of Molecular Interaction Forces

“…Grottel et al on the other hand focus on the molecular surface and visualize electrostatic dipoles through color overlaid on the surface [13]. Khazanov and Carlson exploit tables to communicate molecule interactions [24]. Besides this molecule level visualization, they also communicate the interaction between ligand and binding site through modification of color and van der Waals radii on an atom scale.…”

Real-Time Molecular Visualization Supporting Diffuse Interreflections and Ambient Occlusion

“…More concretely they add contour lines and tooned AO. Khazanov and Carlson provide several visualization elements in the form of tables and tabular graphs [23]. They also visualize the contacts with ligands and their binding sites by modifying the atoms' vdW radii and color proportionally.…”