PCA ETR:ITOUTR PERSPECTIVE INTRODUCTORY FEATURE: SPECIAL

Introduction to the Molecular Recognition and Self-Assembly Special Feature

Julius Rebek, Jr.1 The Skaggs Institute for Chemical Biology and Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037

olecular recognition is a ist. On mixing, these 2 capsules form a and departures for possible future mature branch of chemical hybrid, which is more stable than ei- applications. science, and why shouldn’t ther original capsule. The formation of A switching device is involved in a it be? Decades of studies in the hybrid provides places for guests calyx[6]arene that offers 2 separate physicalM organic chemistry have defined that could not otherwise be accommo- binding sites in the work of Coquie`re et and evaluated the weak intermolecular dated. As in certain schools of archi- al. (6), ‘‘Multipoint molecular recogni- forces involved when 2 molecules en- tecture, reversible encapsulation is less tion within a calix[6]arene funnel com- counter each other. Every bimolecular about the mechanical boundaries of plex.’’ The conformational mobility of reaction, whether it occurs in the gas the walls than it is about the spaces the system allows 3 imidazole arms to phase, dilute solution, or an enzyme’s they define. chelate zinc ions, while 3 aniline nitro- interior, begins with a recognition event. Encapsulation of multiple groups of gens converge to provide a binding site It is an apt time to explore recognition small molecules is the theme of the arti- for a single proton. The space in the in a larger context, that of multicompo- cle by Yamauchi et al. (3), ‘‘Discrete calixarene cavity is shown to bind small nent assemblies, and this special issue of stack of an odd number of polarized molecules such as acetonitrile reversibly. 14 contributions is a beginning. aromatic compounds: The importance of The stress in this molecular device re- Molecules can be made to self-assemble net vs. local dipoles.’’ Three guests with sembles the entatic states proposed for spontaneously into multicomponent, polarized aromatics stack up within a certain enzyme activities. complex structures when they are in- capsule held together by metal/ligand Placing functional groups on the con- structed to do so. The instructions exist interactions. The 3 aromatics arrange cave surface of a molecule is a difficult in the form of the molecule’s shape, its themselves, as clearly shown by X-ray chemical manoeuver, but the article by chemical surfaces, and how well it fills diffraction studies, in such a way that Ballester and Gil-Ramirez (7), ‘‘Self- space in the phase where the assembly the local dipoles cancel. These self- assembly of dimeric tetraurea takes place. These instructions are writ- assembled capsules can make use of calix[4]pyrrole capsules,’’ uses assembly ten into the molecule during its synthe- long or short spacer elements that per- to accomplish just that. Moreover, they sis. Each step in the assembly process is mit different numbers of aromatic guests do so in the much harder environment reversible and dynamic: the complex to stack within the space. of the inner surface of a capsule. Two product is constantly forming and dissi- The electronic environment inside still calyx[4]pyrroles are stitched together pating, and this feature allows for the another capsule is explored in the con- with a cyclic seam of hydrogen bonds to correction of errors as the assembly pro- tribution by Pluth et al. (4), ‘‘Encapsula- provide the capsule. In this host, guests ceeds. Self-assembly implies the distinc- tion and characterization of proton- are presented with the hydrogen-bond tion between ‘‘self’’ and ‘‘nonself,’’ with bound amine homodimers in a water- donors of the pyrroles. The interior recognition and selection between the soluble, self-assembled supramolecular binding sites impart high thermodynamic two during assembly. When 2 different host.’’ These capsules are also held to- and kinetic stability to the host–guest self-assemblies are in the same solution gether by metal/ligand interactions that capsule assembly and hint at opportuni- they may coexist and remain self-sorted result in large overall negative charge in ties for catalysis inside these spaces. or they may hybridize. This molecular the shell provided by the host and stabi- These elegant structures are featured on miscegenation occurs when one compo- lize positively charged guests inside. Us- the cover of this special issue. nent prefers to interact with a compo- ing NMR spectroscopy, Pluth et al. Supramolecular assemblies that show nent other than itself. show it is possible to capture a proton reactive functions are the subject of Several recent studies have shown bound to 2 different amines while inside the article by Kluwer et al. (8), ‘‘Self- many complexes strictly self-sort, and the capsule. These arrangements cannot assembled biomimetic (2Fe2S)-hydroge- this phenomenon is the subject of the be seen in bulk solution where rapid nase-based photocatalyst for molecular contribution by Jiang and Schalley (1), exchange of amine partners at equilib- hydrogen evolution.’’ They describe a ‘‘Integrative self-sorting is a program- rium averages the signals for the many catalyst that produces molecular hydro- ming language for high-level self- species present. gen by using light as the energy source assembly.’’ The article showcases the A molecular device is at the heart of that is transmitted from chromophores application of tandem mass spectrome- the article by Kitagawa et al. (5), ‘‘En- to a diiron-based hydrogenase. This su- try for analysis of complex mixtures in capsulated guest rotation in a self-as- pramolecular approach led to an active the gas phase. Quadruply interlocked sembled heterocapsule directed toward a catalyst that would have been difficult to species are shown to form specific as- supramolecular gyroscope.’’ Here, a re- prepare by traditional synthetic strate- semblies with merciless fidelity. Excep- versibly formed capsule of some com- gies. Catalysis is an intimate and, be- tions to self-sorting in reversibly plexity brings together 2 different resor- cause a moving target (the transition formed capsules appear in the work by cinarenes, 1 bearing acidic and 1 bearing state) is involved, perhaps the ultimate Ajami et al. (2), ‘‘Disproportionation basic groups. The space inside is probed form of recognition. and self-sorting in molecular encapsu- with disubstituted aromatics that are lation.’’ A small spherical capsule that found to spin along the long axis of the binds gases such as methane and a capsule. This ‘‘gyroscope’’ is notional Author contributions: J.R. wrote the paper. longer, cylindrical capsule that binds and at the molecular level, but these The author declares no conflict of interest. molecules such as stilbene do not coex- assemblies provide chemical models 1E-mail: [email protected].

www.pnas.org͞cgi͞doi͞10.1073͞pnas.0905341106 PNAS ͉ June 30, 2009 ͉ vol. 106 ͉ no. 26 ͉ 10423–10424 Downloaded by guest on September 27, 2021 The study by Au-Yeung et al. (9), phyrins coupled with a less familiar organic compounds and pair them with ‘‘Dynamic cominatorial synthesis of a electron deficient aromatic to drive the indicators that give large optical re- catenane based on donor–acceptor in- assembly through the tendency of flat sponses. The 5 steps involved in the pro- teractions in water,’’ takes advantage of molecules to stack on each other. These cess were integrated into a high- the mechanical bond and uses dynamic are characterized in solution by NMR throughput screening method for optical combinatorial synthesis to assemble a and on a mica surface by atomic force analysis. catenane. The symmetrical structure of microscopy. The latter revealed a coiled The article by Macfarlane et al. (14), the catenane contains both electron-rich structure of the fibrous filaments. ‘‘DNA-directed colloidal crystal forma- and -poor surfaces and provides a Biology provides the vehicle and in- tion: Assembly and reorganization,’’ ap- model for intercalation phenomenon in spiration for the article by Martos et al. plies the recognition involved in dsDNA water. This catenane features a record 5 (12), ‘‘Calix[4]arene-based conical- to the directed assembly of nanopar- imbricate and alternating ␲ donor and shaped ligands for voltage-dependent ticles into aggregates. These are used to elucidate processes involved in crystal acceptor units. potassium channels.’’ The C4 symmetry The breadth of self-assembly phenom- of potassium channels mapped neatly on growth and reveal the mechanism of growth for DNA gold nanoparticles. ena is expressed in the study by Deutman a calixarene scaffold. The congruence of In this special issue of PNAS, recogni- et al. (10), ‘‘Squaring cooperative bind- the shapes and the spacing allowed the tion and assembly appear in a broad ing circles.’’ This modern treatment presentation of 4 arginines disguised as spectrum of structural contexts. These of binding cooperativity exposes the dif- guanidinium ions on the calixrene. Salt include mechanically bonded catenanes ficulties in multicomponent receptor– bridges were formed to carboxylates on and rotaxanes, hydrogen-bonded, and guest systems. They use zinc porphyrin/ the protein tetramer. This process led to metal/ligand-bound encapsulation com- pyridine interactions that are embedded the blocking of potassium channels in plexes, salt-bridged biological macromol- in another mechanically bound system, a oocytes and provided a rare application ecules, and open-ended, reversible poly- pseudorotaxane. This experimental ap- of self-assembly in chemical biology. mers held together by aromatic stacking. proach allows apparent cooperativity to The role of neural networks in self- Throughout, chemically synthesized mol- be properly related to the intrinsic ther- assembled systems in high-throughput ecules are central to programmed self- modynamic and kinetic values. screening methods is the subject of the assembly and rely on the intermolecular Polymers based on supramolecular article by Shabbir et al. (13), ‘‘A general forces of recognition between molecules. phenomenon and self-assembly are the protocol for creating high-throughput These interactions are weak and short subject of the article by Haino et al. screening methods for reaction yield and range but their reach is far, because ap- (11), ‘‘Supramolecular polymer formed enantiomeric excess: Applied to hydro- plications can be found in nanoscience, by reversible self-assembly of tetrakis- benzoin.’’ Shabbir et al. devised a sensor materials, devices, sensors, and chemical porphyrin.’’ They use the familiar por- to discriminate between enantiomers of biology.

1. Jiang W, Schalley CA (2009) Integrative self-sorting is 5. Kitagawa H, Kobori Y, Yamanaka M, Yoza K, Kobayashi 10. Deutman ABC, et al. (2009) Squaring cooperative bind- a programming language for high-level self- K (2009) Encapsulated uest rotation in a self-assembled ing circles. Proc Natl Acad Sci USA 10.1073/ assembly. Proc Natl Acad Sci USA 10.1073/ heterocapsule directed toward a supramolecular PNAS.0810145106. PNAS.0809512106. gyroscope. Proc Natl Acad Sci USA 10.1073/ 11. Haino T, Fujii T, Watanabe A, Takayanagi U (2009) 2. Ajami D, Hou J-L, Dale T, Barrett E, Rebek J, Jr (2009) PNAS.0812660106. Supramolecular polymer formed by reversible self- Disproportionation and self-sorting in molecular en- 6. Coquie`re D, et al (2009) Multipoint molecular recogni- assembly of tetrakisporphyrin. Proc Natl Acad Sci USA capsulation. Proc Natl Acad Sci USA 10.1073/ tion within a calix[6]arene funnel complex. Proc Natl 10.1073/PNAS.0809602106. Acad Sci USA 10.1073/PNAS.0811663106. 12. Martos V, et al. (2009) Calix[4]arene-based conical- PNAS.0809903106. 7. Ballester P, Gil-Ramirez G (2009) Self-assembly of shaped ligands for voltage-dependent potassium 3. Yamauchi Y, Yoshizawa M, Akita M, Fujita M (2009) dimeric tetraurea calix[4]pyrrole capsules. Proc Natl channels. Proc Natl Acad Sci USA 10.1073/ Discrete stack of an odd number of polarized aro- Acad Sci USA 10.1073/PNAS.0809612106. PNAS.0813396106. matic compounds: The importance of net vs. local 8. Kluwer AM, et al. (2009) Self-assembled biomimetic 13. Shabbir SH, Regan CJ, Anslyn EV (2009) A general pro- dipoles. Proc Natl Acad Sci USA 10.1073/ [2Fe2S]-hydrogenase-based photocatalys for molecu- tocol for creating high-throughput screening methods PNAS.0810319106. lar hydrogen evolution. Proc Natl Acad Sci USA for reaction yield and enantiomeric excess: Applied to 4. Pluth MD, Fiedler D, Mugridge JS, Bergman RG, Ray- 10.1073/PNAS.0809666106. hydrobenzoin. Proc Natl Acad Sci USA 10.1073/ mond KN (2009) Encapsulation and characterization of 9. Au-Yeung HY, Pantos GD, Sanders JKM (2009) Dynamic PNAS.0809530106. proton-bound amine homodimers in a water-soluble, combinatorial synthesis of a catenane based on donor– 14. Macfarlane RJ, et al. (2009) DNA-directed colloidal crys- self-assembled supramolecular host. Proc Natl Acad Sci acceptor interactions in water. Proc Natl Acad Sci USA tal formation: Assembly and reorganization. Proc Natl USA 10.1073/PNAS.0809806106. 10.1073/PNAS.0809934106. Acad Sci USA 10.1073/PNAS.0900630106.

10424 ͉ www.pnas.org͞cgi͞doi͞10.1073͞pnas.0905341106 Rebek Downloaded by guest on September 27, 2021