Protein-like proton exchange in a synthetic host cavity

Abstract

The mechanism of proton exchange in a metal-ligand enzyme active site mimic (compound 1) is described through amide hydrogendeuterium exchange kinetics. The type and ratio of cationic guest to host in solution affect the rate of isotope exchange, suggesting that the rate of exchange is driven by a host whose cavity is occupied by water. Rate constants for acid-, base-, and watermediated proton exchange vary by orders of magnitude depending on the guest, and differ by up to 200 million-fold relative to an alanine polypeptide. These results suggest that the unusual microenvironment of the cavity of 1 can dramatically alter the reactivity of associated water by magnitudes comparable to that of enzymes.W ater-mediated proton transfer in molecular cavities plays an essential role in the function of nature's remarkable metabolic machinery (1, 2). Of the broad diversity of enzymecatalyzed reactions, those involving transfer of hydrogen are ubiquitous and of high fundamental importance (3). For instance, ATP synthase employs an internal chain of water molecules to mediate proton transfer across an electrochemical gradient (4, 5). This process drives ATP synthesis, which allows organisms to broadly meet their basic energy needs. Recent studies of tunneling in enzymatic hydron transfer reactions have other far-reaching and broad implications, namely the importance of the dynamic enzyme motions in driving catalysis (6, 7).Of the methods used to study hydron transfer, kinetic studies of the mechanisms of amide hydrogen-deuterium exchange (HDX) have helped to elucidate the dynamic interactions between water and protein surfaces that are central to the unique capabilities of enzymes (8-13). Noncovalent interactions, such as electrostatic effects and hydrogen bonding, have also been shown to exert a significant influence on amide HDX rates. These properties are manifest in amide HDX rate constants that can vary by a factor of a billion for residues on the same protein (8). How these variations arise, and how such a property could be harnessed to drive enzyme-like reactivity, remain challenging questions.In a growing effort to emulate the efficacy of biological receptors and enzymes, studies of the preparative, guest-binding, and catalytic properties of synthetic assemblies have been pursued (14-21). Whereas guest encapsulation has been reported in a variety of media, association processes of organic guests are generally more thermodynamically favorable in water (22, 23). Central to these studies is the notion that the displacement of a high-energy water cluster from a receptor drives guest association, and in some cases, subsequent catalysis. However, despite the abundance of structural data documenting diverse water clusters encapsulated in various host cavities, mechanistic descriptions of the dynamic processes between water and host are rare (24-32).As part of the broader field of synthetic hosts previously mentioned, our group has developed a class of biologically inspired, anionic K 12 Ga 4 L 6 assemblies that exhibit cat...

Different and Often Opposing Forces Drive the Encapsulation and Multiple Exterior Binding of Charged Guests to a M4L6 Supramolecular Vessel in Water

“…The assembly contains ah ighly anionic exterior surface, which confers solubility in water,a s well as affinity for the externali on association of cationic molecules. [24] Other catalyzed chemical transformations [25,26] and dramatic changes in the properties and reactivity of encapsulatedg uest molecules [27,28] have been achieved with rate accelerationso f up twentym illion, [29] thus leadingu st oa ssume that the transition state of these reactions is stabilized, similar to the case of enzymes. For example, host 1 catalyzes the Nazarov cyclizationo f1 ,3-pentadienols with rate accelerationso f1 0 6 ,a nd this result has been attributed to transition-state binding, as well as substrate conjugate stabilization.…”

“…These latter investigations led to the development of proton‐catalyzed hydrolysis reactions inside 1 , in which a protonated transition state is stabilized in the host interior . Other catalyzed chemical transformations and dramatic changes in the properties and reactivity of encapsulated guest molecules have been achieved with rate accelerations of up twenty million, thus leading us to assume that the transition state of these reactions is stabilized, similar to the case of enzymes.…”

An isolated water droplet in the aqueous solution of a supramolecular tetrahedral cage

“…The Ga 4 L 6 12− tetrahedral assembly formulated by Raymond and coworkers represents an excellent example of a water-soluble supramolecular cage that has provided host interactions that promotes guest encapsulation. Using steric interactions and electrostatic charge to chemically position the substrate while shielding the reaction from solvent, this host has been shown to provide enhanced reaction rates that approach the performance of natural biocatalysts ( 4 – 10 ). Moreover, aqueous solvation of the substrate, host, and encapsulated solvent also play an important role in the whole catalytic cycle.…”

“…Moreover, aqueous solvation of the substrate, host, and encapsulated solvent also play an important role in the whole catalytic cycle. In particular, the driving forces that release water from the nanocage host to favor the direct binding with the substrate is thought to be a critical factor in successful catalysis, but is challenging to probe directly ( 7 , 8 , 11 – 14 ).…”

Untangling the Diverse Interior and Multiple Exterior Guest Interactions of a Supramolecular Host by the Simultaneous Analysis of Complementary Observables

“…11−13 The metal−ligand framework of the host generates a large and hydrophobic interior cavity capable of encapsulating guest molecules of appropriate size 14 and a highly anionic exterior surface which promotes external association of cationic molecules, and renders the host water-soluble. 15 −17 The interior microenvironment of host 1, which differs dramatically from the bulk solvent environment, has been successfully used to modify the physical properties and reactivity of encapsulated guest molecules 18,19 and to catalyze chemical transformations 20−22 with rate accelerations of up 2 × 10 7 . 23 This catalytic activity is achieved by transition state stabilization in a manner similar to the commonly accepted mechanism of action for enzymatic catalysis.…”