Bimolecular Recognition

The exploitation of the reactivity of molecular crystals lies close to the origins of crystal engineering and is at the heart of the pioneering work of Schmidt [47a]. The idea is that of organizing molecules in the solid state using the principles of molecular recognition and self-assembly. Successful results have been obtained with bimolecular reactions, particularly [2+2] photoreactivity and cyclisation [47b,c]. Another important area is that of host-guest chemistry. 

In biological systems, electron transfer kinetics are determined by many factors of different physical origin. This is especially true in the case of a bimolecular reaction, since the rate expression then involves the formation constant Kf of the transient bimolecular complex as well as the rate of the intracomplex transfer [4]. The elucidation of the factors that influence the value of Kf in redox reactions between two proteins, or between a protein and organic or inorganic complexes, has been the subject of many experimental studies, and some of them are presented in this volume. The complexation step is essential in ensuring specific recognition between physiological partners. However, it is not considered in the present chapter, which deals with the intramolecular or intracomplex steps which are the direct concern of electron transfer theories. 

For this discussion, bioactive peptides will be defined as peptides which interact specifically with a target macromolecular acceptor or are derived from domains involved in a critical protein-protein interaction and, therefore, can compete effectively to mimic or disrupt this bimolecular interaction. Once the structure-activity relationship of a bioactive peptide is revealed, one can identify the termini and/or positions in which introduction of a caging group will be disruptive for target recognition. Alternatively, caging the peptide in an inactive conformation can be accomplished by end-to-end or end-to-side-chain cyclization. 

The utilization of monosubstituted CDs in Scheme 7 presents the drawback that excimer formation depends not only on the concentration of analyte, but also on the bimolecular assembly of the reporter site. The overall signal response of chemosensors of this type therefore depends on the concentration of the analyte and receptor. To alleviate the complication of assembling the reporter site, Ueno and coworkers have appended two monomers to the rim of the CD bucket. The preferred design entails the inclusion of one monomer in the CD bucket. Analyte recognition frees the included monomer, enabling it to interact with its partner tethered to the external rim of the bucket. 

Little is known about the rate of OP binding to tyrosine because the recognition of this OP binding motif is new with the writing of this chapter. Soman binding to Tyr 411 in human albumin has been measured and has been found to be slow with a bimolecular rate constant of 15 3 min (Li et al., 2008a). We expect that other proteins will be identified whose rate of OP binding to tyrosine will be fast. 

The Brownian Dynamics (BD) simulation technique can be used to simulate the diffusion and the association of molecules in solution. BD simulations have been widely used to simulate protein-small molecule and protein-protein association (62). This method may be exploited to simulate the hrst step of molecular recognition when two molecules diffuse from a distance. From such simulations, it is possible to compute the structure and the diffusional encounter complex ensemble and to calculate the bimolecular association rate constant for two diffusing proteins or enzymes and their substrates or inhibitors. In these calculations, the effects of mutations and variations in ionic strength, pH, and viscosity can be investigated (63). 

In many bimolecular reactions the maximum occurs at about 30% of the dissociation energy required to break the original bonds (Hinshelwood, 1941). The essence of the transition state theory (Eyring, 1935) lies in the recognition... 

Rebek and his co-workers have shown that replication - autocatalysis based on molecular recognition - best accommodates the facts observed in the reaction of 42 with 43, and that under the published conditions 44 is responsible for the autocatalysis. The results indicated template-catalyzed replication as the source of autocatalysis, where recognition surfaces and functional groups interact to form a productive termolecular complex. The mechanism demands that catalysis would be absent with esters that lack hydrogen-bonding sites. One complication of this system is that the initial product of this bimolecular preassociative mechanism is postulated to be a cw-amide, which isomerized to the frani-amide, the active form of template. This appears to be one major background reaction for product formation (Scheme 14). 

Pirkle,W. H., Pochapsky,T. C. Chiral molecular recognition in small bimolecular systems a spectroscopic investigation into the nature of diastereomeric complexes,/. Am. Chem. Soc., 1987,109, 5975-5982. 

The frequency with which two reactive species encounter one another in solution represents an upper bound on the bimolecular reaction rate. When this encounter frequency is rate limiting, the reaction is said to be diffusion controlled. Diffusion controlled reactions play an important role in a number of areas of chemistry, including nucleation, polymer and colloid growth, ionic and free radical reactions, DNA recognition and binding, and enzyme catalysis. 

Fritz, M.K. Bailer, H.P. Lang, T. Stmnz, E. Meyer, H.J. Guntherodf E. Delamarche, C. Gerber and J.K. Gimzewski, Translating bimolecular recognition into nanomechanics. Science 288 (2004) 316-318. 

Figure 2.16 Supramolecular complex ofA -(3,5-dinitrobenzoyi)leucine n-propyl amide and methyl A -(2-naphthyl)alaninate. (a) Schematic representation of the three recognition points deduced from NOE data [113]. (b) Stereoview of a bimolecular crystal. The orientation of the two species concurs with solution NOE data. Reprinted with permission from ref. [115].

Di Stefano S, Cacciapaglia R, Mandolini L. Supramolecular control of reactivity and catalysis — effective molarities of recognition-mediated bimolecular reactions. Eur J Org Chem. 2014 7304-7315. 

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