Cellular membrane fusion is thought to proceed through intermediates including docking of apposed lipid bilayers, merging of proximal leaflets to form a hemifusion diaphragm, and fusion pore opening.
The relative binding orientation of tetrahedral intermediate 7 docked in the active site of Pa5106 is different from that of the two inhibitors in the active site.
The early conformational intermediates may dock the target membrane and be responsible for priming the membranes for fusion by inducing critical initial deformations.
IDA, inner dynein arm; ODA, outer dynein arm; DHC, dynein heavy chain; LC, dynein light chain; IC, dynein intermediate chain; DC, docking complex.
The terms of reference for the Committee were for a battleship capable of 21 kn with 12-inch guns and no intermediate calibres, capable of docking in existing drydocks; and a cruiser capable of 25.5 kn, also with 12-inch guns and no intermediate armament, armoured like, the most recent armoured cruiser, and also capable of using existing docks.
The enzymatic parameters of LmPGM have been determined and compared with other PGMs from orthologous species in addition to elucidating its mechanism of action by docking the substrate, intermediate onto the active site.
The simple computational docking results with intermediate 7 support the proposed mechanism.
In practice, it typically gives results of intermediate quality, often better than docking and scoring, but worse than FEP, for example, r = 0.3 for the whole PDB bind database, but r = 0.0 – 0.8 for individual proteins [46].
In the preferred docking pose of intermediate 7, the α-carboxylate group is ion-paired with the guanidino group of Arg-209, whereas in the X-ray structures of compounds 2 and 3, Arg-209 interacts with the side chain carboxylate.
The short (6-residue) helix III has been shown to be unstructured in the intermediate ensemble and does not dock onto the developing hydrophobic core until after the rate-limiting transition state has been traversed.
