A Multi-State, Allosterically-Regulated Molecular Receptor With Switchable Selectivity Jose Mendez-Arroyo, † Joaquín Barroso-Flores, § Alejo M. Lifschitz, † Amy A. Sarjeant, † Charlotte L. Stern, † and Chad A. Mirkin* ,† † Department of Chemistry and International Institute for Nanotechnology, Northwestern University, 2145 Sheridan Road, Evanston, Illinois 60208, United States § Centro Conjunto de Investigació n en Química Sustentable, UAEM-UNAM, Carretera Toluca-Atlacomulco Km 14.5, Unidad San Cayetano, Toluca, Estado de Me ́ xico C. P. 50200, Me ́ xico * S Supporting Information ABSTRACT: A biomimetic, ion-regulated molecular receptor was synthe- sized via the Weak-Link Approach (WLA). This structure features both a calix[4]arene moiety which serves as a molecular recognition unit and an activity regulator composed of hemilabile phosphine alkyl thioether ligands (P,S) chelated to a Pt(II) center. The host-guest properties of the ion- regulated receptor were found to be highly dependent upon the coordination of the Pt(II) center, which is controlled through the reversible coordination of small molecule effectors. The environment at the regulatory site dictates the charge and the structural conformation of the entire assembly resulting in three accessible binding configurations: one closed, inactive state and two open, active states. One of the active states, the semiopen state, recognizes a neutral guest molecule, while the other, the fully open state, recognizes a cationic guest molecule. Job plots and 1 H NMR spectroscopy titrations were used to study the formation of these inclusion complexes, the receptor binding modes, and the receptor binding affinities (K a ) in solution. Single crystal X-ray diffraction studies provided insight into the solid-state structures of the receptor when complexed with each guest molecule. The dipole moments and electrostatic potential maps of the structures were generated via DFT calculations at the B97D/LANL2DZ level of theory. Finally, we describe the reversible capture and release of guests by switching the receptor between the closed and semiopen configurations via elemental anion and small molecule effectors. ■ INTRODUCTION Allosteric control of binding sites in proteins and enzymes plays a major role in the regulation of a diverse array of critical biological processes, such as protein folding 1 and oxygen transport. 2 Enzymatic activity in these processes is often regulated either by controlling the steric profile or the chemical affinity of the binding site for different substrates. 3 The former type of allosteric control is commonly employed to regulate physical access to a binding site, as in the case of protein folding in molecular chaperonins, thus enabling toggling between an active and an inactive state. 4-6 In contrast, the switching between multiple and distinct active states requires the ability to control the chemical affinity of the reactive cavity for a variety of guests without hindering the substrates’ access to it. As such, changes in pH and their associated effects on the structure of hemoglobin are used to regulate the binding of oxygen and carbon dioxide by the same protein, providing an efficient mechanism for the control of gas concentrations in biological tissues. 7,8 In order to mimic the properties and regulatory capabilities of reactive cavities in biological machinery, a number of abiotic counterparts have been developed in which the steric profile and the size of molecular cages are regulated via pH changes, 9-12 photochemistry, 13-16 redox processes, 17-19 and coordination chemistry. 20-30 Such abiotic systems have exhibited the ability to encapsulate and release small organics, 31 therapeutic agents, 32 and biomolecules 33 as a response to changing chemical environment. While the applications of such structures in phase transfer catalysis, 34-36 drug delivery, 37 and sensing 38 have been reported, the usefulness of this approach could be greatly expanded through the development of an abiotic platform to allosterically toggle a single cavitand between an inactive and multiple active states with different recognition properties. However, controlling molecular capsu- les through this approach remains a significant challenge, since regulation must then involve several chemical and structural transformations around the cavitand that must be orthogonal to one another. Herein, we report the synthesis of a novel calix[4]arene ion- regulated receptor assembly whose encapsulation properties can be modulated via small molecule displacement reactions of hemilabile ligands coordinated to d 8 metal centers strategically positioned above the cavitand (Scheme 1). Our design is based on the Weak-Link Approach (WLA) 25,39-41 to the synthesis of supramolecular structures, which has been previously used to construct abiotic allosteric enzyme mimics with applications in sensing, 42,43 signal amplication, 24 and control of catalytic Received: April 14, 2014 Published: July 9, 2014 Article pubs.acs.org/JACS © 2014 American Chemical Society 10340 dx.doi.org/10.1021/ja503506a | J. Am. Chem. Soc. 2014, 136, 10340-10348