Figure 3.

Conformational selection (Ma et al. 1999; Dror and Bahar, 2006) explains why open → close is easier predicted than close → open. Assuming only the protein takes the conformational change but ligand does not in either the bound or unbound state, the binary system, ligand + protein, evolves along the energy landscapes defined by (1) protein conformational change (with or without the contact of ligand) and (2) the binding energy ΔG, only. The conformational change is approximated harmonically by either atomic- or CG-ENM. “Close bound” state herein is referred to as ‘close state’ in the literature. Protein at the ‘open’ state access a close but unbound state (Dror and Bahar, 2006) along the smoothest deformational path (thin line), namely the slowest few normal modes. The protein in the disfavored “close unbound” state may further change the conformation a bit as being ‘induced’ by the ligand which then draws the whole binary system down to a new energy funnel at the big ΔG relief, in the end of the ligand docking. Since the architecture of protein is redefined by the newly formed contacts (Fig. 1 in Tama and Sanejouand, 2001), in either the “close unbound” or “close bound” (more so) state, the energy profiles (dash and solid lines, respectively) change their shape and curvature (mostly narrower) and the groups of atoms that undergo collective motions in the path open → close may not be identifiable again in the path close → open as NMA being performed on both of these close states. Not until the catalytic reaction on the substrate is complete or the ligand is released upon other chemical cues and in turn ‘pushes’ the structure back open, anharmonically, does the protein architecture resume its ‘open’ state again.