Directional preferences of binding

Analyses of packing in crystals have, in many cases, shown that there are directional preferences of binding. The nature of this directionality appears to depend on the partial charges developed on the interacting atoms. Some examples will now be described. 

Surroundings of covalently bound sulfur atoms in crystal structures provide an excellent example of the directionality of intermolecular interactions. Directional preferences of binding around divalent sulfur bonded to two other atoms (XSY where X and Y are commonly carbon) were studied in a wide variety of crystal structures. This was one of the early analyses of intermolecular interactions in crystal structures, before the CSD was generally available [18]. The analysis was made on nonbonded contacts, up to 4.2 A from the sulfur atoms it showed, as indicated in Fig. 5, that the locations of functional groups around the CSC group depend on their (partial) charges. 

Fig. 5a-c Directional preferences of binding of X-S-Y groups a diagram of the directions in which charged groups approach the sulfur atom b chemical formula of mesolanthionine dihydrochloride... 

Fig. 6a-c. Directional preferences of binding of disulfide (-S-S- groups) a diagram of the interactions (Xj, X2, Y, Yj = any atom) b chemical formula of 4,5-bis(methylsulfanyl)-l,2-dithiole-3-thione c stereoview of the S "S interactions in 4,5-bis(methylsulfanyl)-l,2-dithiole-3-thione [112]... 

We are now learning much about intermolecular interactions and reactions from the types of studies described here. An understanding of directional preferences of binding of functional groups is an essential starting point for proposals on mechanisms of reactions between two molecules, large or small, and also for the construction of supramolecular assembHes,be they in solution or in the soUd state, the latter being in the focus of interest here. 

Residue 189 is at the bottom of the specificity pocket. In trypsin the Asp residue at this position interacts with the positively charged side chains Lys or Arg of a substrate. This accounts for the preference of trypsin to cleave adjacent to these residues. In chymotrypsin there is a Ser residue at position 189, which does not interfere with the binding of the substrate. Bulky aromatic groups are therefore preferred by chymotrypsin since such side chains fill up the mainly hydrophobic specificity pocket. It has now become clear, however, from site-directed mutagenesis experiments that this simple picture does not tell the whole story. 

Bogyo, M., Shin, S., McMastee, J. S., and Ploegh, H. L. Substrate binding and sequence preference of the proteasome revealed by active-site-directed affinity probes. Chem Biol 1998, 5, 307-320. 

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