Figure 5.

Binding promiscuity may be achieved with the IF and CS mechanisms. Four different conformers (E, E*, E’, E”) under different ligation states are shown in different scenarios. The different conformers are colored blue, purple, green and teal for E, E*, E’, and E”, respectively. The ‘binding competent’ or binding incompetent’ status differs for each ligand. A) Two IF binding scenarios are depicted wherein two unique ligands have no difference in selection criteria for initial binding. Binding promiscuity can be accomplished by IF when a single conformer binds multiple ligands. Each ligand induces different conformers (E*L or E’L for red and pink ligands, respectively). Potential functional implications are presented in Figure 6A. B) Two CS binding scenarios are depicted wherein two ligand-free conformers, E and E*, exist. E represents a ‘binding competent’ conformer for the red ligand and binding incompetent conformer for the gold ligand. The reverse is true for E*. Thus, binding promiscuity is achieved by CS when members of the ligand free ensemble bind to different ligands. Potential functional outcomes are depicted in Figure 6C. C) Binding promiscuity is achieved for the two conformers E” and E as depicted in Figure 5B, when a multiple ligands individually can bind to multiple conformers. This demonstrates how the functional binding promiscuity may be ‘kinetically’ masked; if the on- and off-rates governing the formation of E”L and EL are equal, then the binding kinetics will appear 2-state. The potential functional implications are presented in Figure 6C.”