The original FORTRAN version of AutoDock was initially tested on a number of protein-substrate complexes which had been characterized by x-ray crystallography 1 . These tests included phosphocholine binding in a antibody combining site, N-formyltryptophan binding to chymotrypsin and N-acetylglucosamine binding to Lysozyme. In almost all cases the results of the AutoDock simulations functionally reproduced the crystallographic complexes. In further applications AutoDock was used to predict interactions of substrates with aconitase prior to any crystallographic structures for complexes. In this work we not only predicted the binding mode of isocitrate, but we demonstrated the utility of AutoDock in generating substrate models during the early stages of crystallographic proteins structure refinement 2 . Citrate docking experiments showed two binding modes, one of which approximated the experimental electron density determined for an aconitase-nitrocitrate complex. The docking simulation results provided insight into the proposed reaction mechanism of the enzyme.
One novel and intriguing use of the software was reported from Koshland's laboratory 3 . These investigators used the known structures of the maltose-binding protein (MBP) and the ligand binding domain of the aspartate receptor to predict the structure of the receptor-protein complex (see diagram below). They used knowledge from mutational studies on MBP to select two octapeptides on the protein known to be involved in the binding to the aspartate receptor, which they docked independently to the model of the receptor using our automated docking code (the backbones of the peptides were fixed, but the side-chain conformations and overall orientations were unrestrained).
The distance and orientation of the two peptides as docked to the receptor corresponded to that in the intact MBP, thus enabling a reasonable prediction of the protein-receptor complex. This technique could be generally useful in situations where there are data on multi-site interactions.
1. Goodsell, D.S. & Olson, A.J. (1990) "Automated Docking of Substrates to Proteins by Simulated Annealing", Proteins: Str. Func. Genet. , 8 , 195-202.