Conformation-dependent site

D-QSAR. Since compounds are active in three dimensions and their shape and surface properties are major determinants of their activity, the attractiveness of 3D-QSAR methods is intuitively clear. Here conformations of active molecules must be generated and their features captured by use of conformation-dependent descriptors. Despite its conceptual attractiveness, 3D-QSAR faces two major challenges. First, since bioactive conformations are in many cases not known from experiment, they must be predicted. This is often done by systematic conformational analysis and identification of preferred low energy conformations, which presents one of the major uncertainties in 3D-QSAR analysis. In fact, to date there is no computational method available to reliably and routinely predict bioactive molecular conformations. Thus, conformational analysis often only generates a crude approximation of active conformations. In order to at least partly compensate for these difficulties, information from active sites in target proteins is taken into account, if available (receptor-dependent QSAR). Second, once conformations are modeled, they must be correctly aligned in three dimensions, which is another major source of errors in the system set-up for 3D-QSAR studies. 

Balass M, Heldman Y, Cabilly S, Givol D, Katchalski-Katzir E, Fuchs S, Identification of a hexapeptide that mimics a conformation-dependent binding site of acetylcholine receptor by use of a phage-epitope library, Proc. Natl. Acad. Sci. USA, 90 10638-10642, 1993. 

A fundamental difference between 3D- and a 2D-QSAR equation is the non-existence of conformational dependent secondary sites in the latter. Hence, a direct transposition of 3D- and 2D-models is not always possible but the global properties of the chemical structures, if relevant to the activity, may show their presence in both of them. Moreover, in a broader perspective, all 2D-QSAR parameters—physicochemical as well as structural—can be considered as one or the other form of global descriptors. In light of this, to bridge the 2D- and 3D-features the following 2D-QSAR equations have been derived for the antifungal activity of 2,3,4-substituted thiazolidines (Table 21). 

When codon-anticodon base pairing occurs the amino acid attached to the tRNA is correctly positioned within the ribosome for peptide bond formation. As each peptide bond is formed, the newly incorporated amino acid is released from its tRNA and the mRNA moves relative to the ribosome so that a new codon enters the catalytic site. The latter process is called translocation. Translation continues one codon at a time until a special base sequence, called a termination or stop codon, is reached. The polypeptide is then released from the ribosome, and folds into its biologically active conformation. Depending on the type of polypeptide, it may then bind to other folded polypeptides to form larger complexes. 

Fig. 21.4. Binding change mechanism for ATP synthesis. The three ap subunit pairs of the ATP synthase headpiece have binding sites that can exist in three different conformations, depending on the position of the 7 stalk subunit. Step 1 When ADP + Pi bind to an open site and the proton influx rotates the 7 spindle (represented by the arrow), the conformation of the subunits change and ATP is released from one site. (ATP dissociation is, thus, the energy-requiring step). Bound ADP and Pi combine to form ATP at another site. Step 2 As the ADP + Pi bind to the new open site, and the 7 shaft rotates, the conformations of the sites change again, and ATP is released. ADP and Pi combine to form another ATP.

Possible effects on soluble protein of immobilization. Protein is shown as having three antigenic sites (epitopes). Two are linear (solid box and shaded pentagon), and one is conformational dependent (shaded oval). 

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