From Selection to Instruction and Back - Competing Conformational Selection and Induced Fit Pathways in Abiotic Hosts.

Two limiting cases of molecular recognition, induced fit (IF) and conformational selection (CS), play a central role in allosteric regulation of natural systems. The IF paradigm states that a substrate "instructs" the host to change its shape after complexation, while CS asserts that a guest "selects" the optimal fit from an ensemble of preexisting host conformations. With no studies that quantitatively address the interplay of two limiting pathways in abiotic systems, we herein and for the first time describe the way by which twisted capsule  M - 1,  encompassing two conformers  M - 1 (+) and  M - 1 ( - ), traps CX 4  (X = Cl, Br) to give CX 4 Ì M - 1 (+)   and   CX 4 Ì M - 1 ( - ), with all four states being in thermal equilibrium. With the assistance of 2D EXSY, we found that CBr 4  would, at its lower concentrations, bind  M - 1  via  M - 1 (+)→ M - 1 ( - )→CBr 4 Ì M - 1 ( - ) pathway corresponding to conformational selection. Nudged elastic band (NEB) coupled with density functional theory (DFT) computations revealed the mechanism of  M - 1 ( - )/ M - 1 (+) interconversion from which we deduced that the reduced rate for CX 4 Ì M - 1 ( - ) converting   into   CX 4 Ì M - 1 (+) resulted from favorable C-H···Cl/Br-C host-guest contacts stabilizing the corresponding ground state. For  M - 1  complexing CCl 4  though,   we used data from 2D EXSY measurements and 1D NMR lineshape analysis to characterize the dynamics of every elementary step in the four-state equilibrium. Subsequently, the contribution of IF and CS was determined using flux analysis wherein the mass transport (i.e. flux) through each particular pathway was quantified. Importantly, we found that lower CCl 4  concentrations would favor CS while the IF pathway prevailed at higher proportions of the guest.