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We present a rationale and proposed approach to the modification and development of bind sites using their respective cognate ligands as template. This is in support of a plausible “instructive” role for the ligand and therefore its involvement in determination of the structure and properties of bind sites. We emphasize the relationship between substrate and active site as an example of the relationship between ligand and bind sites, respectively. This is based on the assumption that there are shared features between all ligand:bind site complexes. Therefore, principles that apply to a specific complex can be applied, in general, to other protein-based complexes. We define ligand-associated probability bias as the difference between the probability of finding activity-determining conformations (ADCs) in the presence- and absence of ligands. For cognate ligands, the given bias is in favor of these ADCs. Thus, bind sites are more likely to assume ADCs when their cognate ligands are present. We relate such probability bias to structural reorganization, disorganization, and preorganization events. We then propose a means of deriving an [apparent] preorganized bind site structure by way of reorganization events that occur with cognate ligand. Finally, we propose a means of deriving an [actual] preorganized bind site structure by way of reorganization events that occur with cognate ligand, albeit during the folding process. The assumption is that the role of the ligand in derivation of such [actual] preorganized bind site structures is an instructive role, and is in support of the Haurowitz-Pauling hypothesis.
This is a second version for the preprint: A template-based approach to the modification of binding properties of globular proteins II:Rationale and proposed approach. An important section (key considerations when attempting verification of the stated schema) has been added to the original submission. As the name implies, this section presents key factors that should be considered when attempting experimental verification of the use of cognate ligand(s) in affecting the structure of protein bind sites.