JOURNAL OF MOLECULAR RECOGNITION, zyxwvuts VOL. 9. zyxwvu 123-1 32 zyxwvut ( 1996) Experimental Results from Host-Guest Complexes for the Design of Effectors in Biological Systems and of Enzyme Analogous Catalysts Hans-Jorg Schneider*, Frank Eblinger, Joachim Sartorius, Jorg Rammo FR Organische Chemie der UniversitSt des Saarlandes, D 66041 Saarbriicken, Germany Strategies and results for the extraction of biologically important non-covalent binding increments from studies of synthetic host-guest complexes are described with selected examples. Systematic analyses of association constants and the corresponding complex conformations in solution allows us zyxwvu to assign specific values to different pairwise interactions, including salt bridges, amide-type hydrogen bonds, van der Waals effects, and metal ion interactions. A comparison of association constants between selected flexible and rigid ion pairs shows few differences, indicating that different entropy contributions either are small, or cancel with corresponding enthalpy changes, at least in weakly bound complexes. The supramolecular design of enzyme-analogous catalysts is illustrated with complexes containing, e.g. strongly bound yet still active Ln” ions, e.g. in an azacrown ether, and groups which support association with nucleic acids and can serve as nucleophiles. The experimentally observed hydrolysis rate enhancements with such artificial nucleases amount to lo6 and more, both with phenyl phosphates and with ds-DNA. Keywords: supramolecular complexes; enzyme analogues; hydrogen bonds; salt bridges; catalysis; linear free energy relation; artificial nucleases Introduction zyxwvu Molecular recognition has always been associated with complementary shape between host and guest molecules. However, geometric fit is no more than a certainly important prerequisite for the action of suitablefunctions which hold receptor and effector together, and are needed to bring a supramolecular system into action. The concept of lead structures, and the identification of pharmacophors in medicinal chemistry, has always implied the search for functionalities which are complementary to a molecular target, even before the term molecular recognition became popular in modem chemistry. It remains one of the most important tasks for the rational design of drugs, of signal- giving devices, of molecular switches, and of enzyme-analogous catalysts, to provide numerical data for the energies involved in complex formation, based on the analysis of individual interactions between different donor and acceptor groups. The availability of such data will also help the understanding of natural complexes, as well as the development of suitable force field potentials and para- metrizations for computer-aided molecular modelling. Painvise contributions to the total binding between biopolymers and effector molecules have been analysed almost 25 years ago by Page and Jencks (1971). Interactions between single functions in protein-ligand complexes were identified particularly after many data on enzyme-inhibitor It To whom correspondence should zyxwvutsr be addressed. associations became available (Goodford, 1985; Boobyer et al., 1989; Andrews et al., 1984; Rotstein and Murko 1993; Meng et al., 1992; Tidar and Karplus, 1991; Bohm, 1992, 1994; see also Empie and Laskowski, 1982). With few exceptions little effort has been made until today to extract free energies for binding contributions of the participation functions from measurements with biopolymers. As will be illustrated later, this is indeed difficult in view of the uncertainties in the exact structure and local environment in binding sites of, for instance, proteins. Lancet, Horovitz and Katchalski-Katzir (1994) have drawn an interesting parallel between the problems involved in the reductionist analysis of social group behaviour and protein-ligand interactions. In both cases a single intervention, or pertubation-such as exchange of single amino acids in engineered proteins- often leads to changes not related uniquely to the component under study. In contrast, synthetic host-guest complexes (Lehn, 1988; Cram, 1988) offer a broad range of conformationally better defined systems, for which also the microenvironment (neighbour groups, solvents, salts, etc.) can be changed under better defined conditions. The major advantage is that one can design artificial receptor complexes so as to obtain the desired information about energetic values of inter- actions in supramolecular systems (Schneider, 1991 a; Schneider, 1994). The conformational conditions can be evaluated by NMR spectroscopy, which in synthetic complexes is again easier than in biopolymers. It is the purpose of the present short review to illustrate this CCC 0952-3499/96/020123- I0 @ 1996 by John Wiley & Sons, Ltd. zyxwvutsrq Accepted 3 October I995