STALK: A Molecular Docking System

In this work, part of a joint project between the Center for Mechanistic Biology and Biotechnology and the Mathematics and Computer Science Division, we are studying the docking of a ligand molecule into a protein binding site. The problem is posed as an optimization problem where the objective is to minimize the intermolecular interaction energy between the two molecules. Because the possible number of conformations between the two molecules can be very large, we are using genetic algorithms to explore the space of possible conformations. The ability to solve such problems will be of great value in rational drug design; as computing power increases problems of protein-protein interactions and ultimately self-assembly processes can be addressed.

In pursuit of these goals, we are developing the STALK molecular docking system. STALK uses the PGAPack parallel genetic algorithm library to search for a low-energy conformation. An interface to the CAVE virtual reality system allows a scientist to (1) visualize the genetic algorithm's progress and, (2) interact with the algorithm by, for example, changing the position or structure of the drug molecule and restarting the algorithm so that the new parameters are incorporated.

The images below are taken from the CAVE simulator. They are from a study we are carrying out of the docking of Ribonuclease S. Ribonuclease S is a well-characterized protein composed of two subunits of unequal size. Ribonuclease S is formed by the cleavage of the peptide bond between positions 20 and 21 of Ribonuclease A. We are using the helix-forming S-peptide as a model ligand that binds to the model receptor represented by the S-protein, consisting of 104 amino acids. Shown are a truncated form of the S-peptide (purple) and the S-protein (colored by atom type). Coordinates are taken from the Brookhaven Database entry, 1RBH. See Varadarajan & Richards, "Crystallographic structures of Ribonuclease S variants with nonpolar substitution at position 13: packing and cavities," Biochemistry 31: 12315, 1992.

S-protein and S-peptide with highlighted sidechain

S-protein and S-peptide with menu displayed

View from inside

CAVE shot 1

CAVE shot 2