Figure 2.

Snapshots from molecular dynamics simulations of inhibitor bound and free protease, and from simulations following the manual docking of the inhibitor into the binding site. The ‘closed’ conformation (a) is represented by ensemble of closed structures with high similarity (f). In contrast, the ‘semi-open’ conformation (b) represents a much more flexible ensemble (g) with larger fluctuations of the flaps. Those eventually lead to full opening of flaps (c, d); the open form is transient and returns to semi-open conformation (e). When the inhibitor is manually placed into a binding site (h), it induces an asymmetric flap closure with initial closing of one of the flaps (i) and finally converting to fully closed form (j) with flaps pulled into the binding site and flap handedness appropriate for the closed state.