Abstract
This article is of two parts: (a) the development of a protein reduced representation and its implementation in a Web server; and (b) the use of the reduced protein representation in the modeling of the binding site of a given ligand and the screening for the model in other protein 3D structures. Current methods of reduced protein 3D structure representation such as the Ca trace method not only lack essential molecular detail, but also ignore the chemical properties of the component amino acid side chains. This chapter describes a reduced protein 3D structure representation called “double-centroid reduced representation” and presents a visualization tool called the “DCRR Web Server” that graphically displays a protein 3D structure in DCRR along with non-covalent intra- and intermolecular hydrogen bonding and van der Waals interactions. In the DCRR model, each amino acid residue is represented as two points: the centroid of the backbone atoms and that of the side chain atoms; in the visualization Web server, they and the non-bonded interactions are color-coded for easy identification. The visualization tool in this chapter is implemented in MATLAB and is the first for a reduced protein representation as well as one that simultaneously displays non-covalent interactions in the molecule. The DCRR model reduces the atomicity of the protein structure by ~75% while capturing the essential chemical properties of the component amino acids. The second half of this chapter describes the application of this reduced representation to the modeling and screening of ligand binding sites using a data model termed the “tetrahedral motif.” This type of ligand binding site modeling and screening presents a novel type of pharmacophore modeling and screening, one that depends on a reduced protein representation.
TopMethods
This report essentially consists of two parts, namely (a.) the implementation of the protein double-centroid reduced representation and the creation of a web server for it, and (b.) the development of a ligand binding site modeling method and screening for such model in any given protein 3D structure.
Key Terms in this Chapter
Ligand Binding Site: The specific site on a protein, usually a crevice or a pocket of varying depth, where a ligand binds in a specific geometry and orientation, and with high affinity
Pharmacophore Modeling: The extraction of the essential geometric and electrostatic (i.e., chemical) properties of a ligand, preferably in the form of a specific data structure for computational input, that are essential for its biological function; an important step in LBS screening and drug design
3D Search Motif: A 3D motif that is encoded in a computer program to be used for screening structures, usu. of proteins, using a search algorithm; in the present context, this is the tetrahedral motif corresponding to a LBS
Tetrahedral Motif: the reduced representation of a particular LBS composed of four points which are centroids of the backbone or sidechain atoms in the protein contacting the ligand via H-bonding or VDW interaction at its LBS; on vertex is denoted as the ’root’, and the other three ’nodes’ 1, 2 and 3.
Centroid: In the sense used this article, the unweighted geometric centroid of a group of neighboring atoms, considering only their x-, y-, and z-coordinates, and without consideration of their atomic masses
Double-Centroid Representation: A protein 3D reduced representation wherein each amino acid is represented by two centroids: that of the backbone atoms (N, Ca, C’, O) and that of the sidechain atoms (Cß and beyond)
Reduced Representation: A method of representing macromolecules, usually with a visual component, where the atomicity (number of coordinates) is significantly reduced compared to the all-atom representation (usually derived from an x-ray crystallographic model)
Pharmacophore: A subset of the 3D structural features of a ligand that are specifically recognized at its binding site in its cognate protein receptor molecule and are essential for its biological action(s)
3D Motif: A specific local 3D arrangement of specific protein atoms (from its backbone or side chains) created when they are brought close together in space by protein folding; the residues involved may or may not be contiguous in primary sequence