Predicting protein-protein and protein-ligand docking remains one of the 
challenging topics of structural biology. The main problems are (i) to reliably 
estimate the binding free energies of docked states, (ii) to enumerate possible 
docking orientations at a high resolution, and (iii) to consider mobility of the 
docking surfaces and structural rearrangements upon interaction. Here we present 
a novel algorithm, TreeDock, that addresses the enumeration problem in a 
rigid-body docking search. By representing molecules as multidimensional binary 
search trees and by exploring a sufficient number of docking orientations such 
that two chosen atoms, one from each molecule, are always in contact, TreeDock 
is able to explore all clash-free orientations at very fine resolution in a 
reasonable amount of time. Due to the speed of the program, many contact pairs 
can be examined to search partial or complete surface areas. The deterministic 
systematic search of TreeDock is in contrast to most other docking programs that 
use stochastic searches such as Monte Carlo or simulated annealing methods. At 
this point, we have used the Lennard-Jones potential as the only scoring 
function and show that this can predict the correct docked conformation for a 
number of protein-protein and protein-ligand complexes. The program is most 
powerful if some information is known about the location of binding faces from 
NMR chemical-shift perturbation studies, orientation information from residual 
dipolar coupling, or mutational screening. The approach has the potential to 
include docking-site mobility by performing molecular dynamics or other 
randomization methods of the docking site and docking families to families of 
structures. The performance of the algorithm is demonstrated by docking three 
complexes of immunoglobulin superfamily domains, CD2 to CD58, the V(alpha) 
domain of a T-cell receptor to its V(beta) domain, and a T-cell receptor to a 
pMHC complex as well as a small molecule inhibitor to a phosphatase.