The repeating disaccharide unit of many GAGs, including heparin, heparan sulfate (HS), and dermatan sulfate (DS), contains iduronic acid (IdoA), a hexopyranose which is known to adopt several conformations (C1, C4, and S o ).
Previous MD simulations of pure TO systems in crystalline or amorphous states showed that the molecules could adopt several conformations including the tuning fork (sn1 and sn3 tail parallel, and sn2 antiparallel), the chair (sn1 and sn2, or sn2 and sn3 parallel, and the other tail antiparallel), the trident (all tails parallel) or the liquid (chains pointing in random directions) [32].
Alternatively, this region could be flexible and adopt several conformations at the virion surface, only some of which are recognized by specific neutralizing antibodies.
However, the free energies computed here have been averaged over several conformations generated through MD simulations, and hence the effects of entropy to some extent are implicitly included in the current calculations.
The substrate stabilizes one of the several conformations accessible to the protease functionally and energetically favorable (from both thermodynamic and kinetic aspects).
Notably, several conformations have been solved, including open and closed channels with distinct global tertiary and quaternary structure.
A comparison of the structures suggests that the conformation of the N-terminal segment is not highly restricted in the complex and may adopt several conformations.
The ligand pocket is closed on one side by an antiparallel β-sheet and on the other by H12, known to be directly involved in the transactivation function AF-2 by mutagenesis studies [ 15], and for which several conformations ('agonist' or 'antagonist' conformations) have been evidenced [ 16].
Several conformations of the unlabeled CP04 were generated and then docked to the CCK-2R homology model by using AutoDock Vina [26].
