INSTRUMENTATION completed for optimization; it is a problem of interfacial chemical analysis at the molecular level. The deficiencies in our knowledge are compounded by the large variety of immobilization techniques and binding agents that are used. Perhaps researchers should concentrate on a limited number of the best techniques so as to build a generic methodology of surface modification (e.g., immobilization of Fab) and actively pursue promising areas such as deposition onto "fluid" or highly mobile surfaces (to avoid site-specific denaturation). The extensive use of enzymes and antibodies in biosensors has been driven by availability, not suitability. Nature does not employ these different active chemical species for sensing purposes. Enzymes catalyze reactions, and antibodies bind with toxins to accelerate removal or to initiate destruction of an invading organism in some linked mechanism (e.g., a complement system). Molecular receptors provide insight into the molecular requirements associated with chemical sensing (36). These systems bind ligands by using interactions similar to those encountered for antibody-antigen binding, and they undergo conformational changes in a manner similar to en-
zymes, providing selectivity and reversibility. More of the receptors used in the future will be derived synthetically by using techniques such as genetic engineering to obtain catalytic antibodies, idiotypic sites, and modifications of proteins encountered in natural systems. These receptors will still be based on protein structure, and their reliability will be limited by denaturation of tertiary structure and nonselective binding induced by availability of relatively large molecular surface areas. Synthetic chemistry may provide selective binding surfaces that are not prone to denaturation and drift of binding activity, but it is unclear whether the conformational changes associated with reversibility can be designed in these systems. The dynamics of the selective site may present the most serious obstacle to practical implementation of biosensor technology. Molecular mobility provides selectivity, reversibility, and analytical signal but also causes interference and denaturation, which ultimately leads to lack of confidence in the signal. Nature has overcome the obstacle imposed by denaturation and irreversible binding of interfering species by continually replacing proteins
in living organisms, sweeping defective receptors into the recycling system. How an equivalent regeneration process, or accurate dynamic calibration, will be achieved in the field of biosensors remains unanswered. Some researchers believe a solution may exist in the use of living cells as selective reagents. Obviously this route is fraught with problems such as environmental stability, life cycles, metabolism, and toxins. It is important that biosensor specialists accelerate efforts to address these fundamental problems, especially in light of the scientific community's concern that these problems may be insoluble. References (1) Levitzki, A. Receptors, A Quantitative Approach; Benjamin/Cummings Publishing Co.: Menlo Park, CA, 1984. (2) Bonchev, D.; Trinajstic, N. Int. J. Quantum Chem. Symp. 1982,16, 463. (3) Bertz, S. H. J. Am. Chem. Soc. 1981, 103, 3599. (4) Dosmorov, S. V. Proceedings of the Fifth Ail-Union Conference on Uses of Computers in Molecular Spectroscopy and Chemical Research; Novosibirsk, USSR, 1980; p. 28. (5) Janin, J.; Chothia, C Biochem. 1978,15, 2943. (6) Simon, Z. Quantum Biochemistry and Specific Interactions; Abacus Press:
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404 A · ANALYTICAL CHEMISTRY, VOL. 63, NO. 7, APRIL 1, 1991
