Peptide Conformation and Biological Activity

The data currently available strongly suggests that predominate solution conformation does not directly correspond to the biologically active conformer. Receptors either induce the conformation required for recognition and activation, or select a minor conformer from the ensemble available in the solution. A similar conclusion based on conformational studies on gramicidin S analogs with equivalent biological activity, but with distinctly different conformations. Structure–activity studies of peptides have ignored the conformational effects of chemical modification. This review emphasizes on how these may be used to distinguish between solution and receptor-bound conformations. Nuclear magnetic resonance offers the ability to assign a resonance signal to each nucleus of the peptide molecule under study and interpret the chemical shift, relative intensity, and splitting patterns of these resonance signals in terms of angles and rotational freedom about bonds and proximity of different groups. Unfortunately, most of the times, the interpretation of the results is clouded by hidden assumptions and technical requirements that are not ideal. A peptide would be expected to tolerate less distortion than a segment of a protein chain as the end residues can be moved without sacrificing a large number of energetically favorable inter-actions to relieve the local strain. A basic assumption of a common backbone conformation that orients the essential functional group in the correct spatial positions for all active analogs underlies this approach. Intersection of the set of all possible conformations for each analog contains the biologically active conformer. Identification of the essential functional groups by traditional structure–activity studies allows the transformation of the problem from conformational space to the orientation space where pharmacophores analysis is possible— that is, required groups and their orientation, and removes the objection of a possible analog with a different conformation having activity. To illustrate these concepts, the current state of knowledge of conformation of three peptide hormones is reviewed in this chapter.