A flexible ligand docking protocol based on a divide-and-conquer strategy i
s investigated. This approach first separates total search space into confo
rmation and orientation space. It uses a grid-based method to sample the co
nformation of an unbound ligand and to select the low-energy conformers. Ri
gid docking is then carried out to locate the low-energy binding orientatio
ns for these conformers. These docking structures are subsequently subjecte
d to structure refinement including molecular mechanics minimization, confo
rmational scanning at the binding site and a short period of molecular dyna
mics-based simulated annealing. This approach has been applied to twelve li
gand-protein complexes with three to sixteen rotatable bonds. The docked lo
west-energy structures have root mean square deviations ranging from 0.64 A
ngstrom to 2.01 Angstrom with respect to the corresponding crystal structur
es. The effect of atomic charges and van der Waals parameters on the dockin
g results, and the role of the dielectric constant in the conformation samp
ling are discussed in detail. A fragment-based docking approach that takes
advantages of the divide-and-conquer strategy has also been explored and th
e results are compared with those produced by a whole molecule-based approa
ch. Proteins 1999;36:1-19. (C) 1999 Wiley-Liss, Inc.