Force computations in automated docking

Automated docking refers to the problem of computing the optimal complementary fit of two molecules---a macromolecular receptor such as DNA or protein and a small molecule of interest (ligand). AutoDock is a docking software that computes the receptor-ligand binding energy to rank docked ligands. In this work, AutoDock's grid-based method for energy evaluation was exploited to complement the binding energies with computed forces on docked ligand atoms. These forces and energies helped to provide insights into enzyme-substrate interaction mechanisms of three different enzymes--- Hypocrea jecorina Cel7A, a cellobiohydrolase, Fusarium oxysporum Cel7B, an endoglucanase, and Saccharomyces cerevisiae alpha-1,2-mannosidase. Cel7A and Cel7B are cellulose-degrading enzymes that, based on structural homology, belong to glycoside hydrolase Family 7. Cel7A binds crystalline cellulose and processively breaks cellobiose units from chain ends, while Cel7B targets amorphous cellulose and makes internal breaks in cellulose chain with limited processivity. The processive force on the substrate docked to the Cel7A catalytic domain (CD) is greater than twice that on the substrate docked to the Cel7B CD, explaining the difference in their processive behavior. Cel7A has a two-domain structure with a CD and a cellulose binding domain (CBD) joined by a highly glycosylated linker. Based on the interaction energies and forces on cellooligosaccharides docked to the CD and CBD, we propose a molecular machine model where the CBD wedges itself under a free chain end on the crystalline cellulose surface and feeds it to the CD active-site tunnel. alpha-1,2-Mannosidase from the endoplasmic reticulum, a Family 47 glycosyl hydrolase, is a key enzyme in the N-glycon synthesis pathway. AutoDock was used to dock alpha-D-mannopyranosyl-(1,2)-alpha-D-mannopyranose with its glycon in chair (1C4, 4C1), half-chair (3 H2, 3H4, 4H3), skew-boat (O S2, 3S1, 5S1), boat (2,5 B, 3,OB, B 1,4, B2,5), and envelope (3 E, 4E, E3, E4) conformations. Both docked energies and forces on docked ligand atoms were calculated to determine how the ligand distorts to the transition state. From these, we can conclude that the most likely binding pathways are 1C4 → 3H2 → OS 2 → 3,OB → 3 S1 → 3E and OS2 → 3,O B → 3S1 → 3E with 1C4 and OS2 as starting conformations, respectively.