Complementarity of structure

In the experiment, the components of the new replicator were mixed with the components of our biphenyl replicator [42], and we expected to generate four self-complementary, replicating systems. We assumed that self-complementarity of structure was sufficient for replication after all, had not all our replicators (and those of others [43]) shared this feature All possible combinations of (4), (8), (41) and (40) were duly synthesized (Figure 25), and their behavior taught us a lesson concerning molecular shape. One of the shuffled replicators, the adenine-thymine product (43), resembles DNA, but with an amide backbone. It turned out to be the most effective synthetic replicator we have encountered to date (perhaps this is not mere coincidence). The other shuffled replicator (44) was unable to catalyze its own formation. 

In conclusion, one important factor that contributes to the strong affinity of TBP proteins to TATA boxes is the large hydrophobic interaction area between them. Major distortions of the B-DNA structure cause the DNA to present a wide and shallow minor groove surface that is sterically complementary to the underside of the saddle structure of the TBP protein. The complementarity of these surfaces, and in addition the six specific hydrogen bonds between four side chains from TBP and four hydrogen bond acceptors from bases in the minor groove, are the main factors responsible for causing TBP to bind to TATA boxes 100,000-fold more readily than to a random DNA sequence. 

Medicinal chemists have a distinct advantage in pursuing mechanism-of-action studies because it is possible to synthesize a series of structurally related congeners and measure their biological activity. A correlation between activity and particular structural features not only helps to identify the pharmacophore, or active moiety imbedded within the molecule, but also may establish critical requirements or complementarity for the biological target or receptor for the particular drug class. 

Figure 19.7 Molecular correspondence of the inorganic-organic interface in the nacreous shell layer of Nautilus repertus. (a) Structural relationships between protein sheets, aragonite crystals and chitin fibres, (b) Possible complementarity of Ca binding. (From Mann et al., 1989. Reproduced with permission from John Wiley Sons., Inc.)...

Once the protein interaction pattern is translated from Cartesian coordinates into distances from the reactive center of the enzyme and the structure of the ligand has been described with similar fingerprints, both sets of descriptors can be compared [25]. The hydrophobic complementarity, the complementarity of charges and H-bonds for the protein and the substrates are all computed using Carbo similarity indices [26]. The prediction of the site of metabolism (either in CYP or in UGT) is based on the hypothesis that the distance between the reactive center on the protein (iron atom in the heme group or the phosphorous atom in UDP) and the interaction points in the protein cavity (GRID-MIF) should correlate to the distance between the reactive center of the molecule (i.e. positions of hydrogen atoms and heteroatoms) and the position of the different atom types in the molecule [27]. 

Obviously, strong binding of the substrate to the catalyst may distort the structure of S towards that of TS, thereby making reaction easier. However, such distortion simply reflects the complementarity of the catalyst and the transition state (Fersht, 1985). From a purely thermodynamic point of view, the formation of a strong S-catalyst complex lowers free energy by an additional amount that must be overcome in the process of activation of the kc process (3) (Fig. 2). Living organisms and their enzymes have evolved so... 

Henkel T, Brunne RM, Muller H, Reichel F. (1999) Statistical investigation into the structural complementarity of natural products and synthetic compounds. Angew Chem Int Ed 38 643-647. 

Figure 3/ for example/ places the lanosterol so as the 3f hydroxyl polar group lies over the propionate side chains. To reduce the complexity of this picture one can now replace the lanosterol structure by a surface canopy to represent the extent of the hydrophobic substrate binding site. There is also the facility to code this surface to signify the electronic properties of the substrates such as their electron density/ electrostatic potential/ or HOMO/LUMO values. Theoretical work of this type is currently suggesting quite remarkable complementarity of electron properties between bound substrates and protein binding sites. (10). 

The demonstration that stars are capable of such nuclear fertihty is based upon a combination of knowledge from what appear to be widely separated areas of physics. One of these concerns the internal structure of stars, telling us the temperature and pressure at different depths. The other concerns the probabilities at different energies of all the possible reactions between various nuclei, and between those nuclei and protons or neutrons. In the latter case, the acquisition of the relevant data was greatly accelerated by the Second World War. The beauty of nuclear astrophysics rests upon the success of this marriage and the complementarity of the two disciplines it brings together. The nuclear butterfly has returned to its stellar chrysalis. 

Both in nature and in test tubes many complicated reactions take place with apparent ease. Highly specific enzymatic reactions involving complementarity of substrate and receptor both with respect to their spatial structure and electrostatic fields lie outside the scope of this book. Here we would like only to mention a few... 

The action of most enzymes is inhibited by many substances. Inhibition is often specific, and studies of the relationship between inhibitor structure and activity have been important to the development of our concepts of active sites and of complementarity of surfaces of biomolecules. Inhibition of enzymes is also the basis of the action of a very large fraction of important drugs. Inhibition may be reversible or irreversible, the latter leading to permanent inactivation of the enzyme. Often, but not always, irreversible inhibition is preceded by reversible binding of the inhibitor at a complementary site on the enzyme surface. 

---