Aspects of the Design of Conformationally Constrained Peptides

This chapter discusses different aspects of the design of conformationally constrained peptides. It also describes the use of nuclear magnetic resonance (NMR)-generated parameters for static and dynamic structures in conjunction with modern theoretical calculations as a general strategy for the design of bioactive and selective peptides. The general approach to conformational analysis of peptides in solution includes the following steps: (1) the absolute assignment of NMR signals to the peptide components (residues); (2) the extraction of various NMR parameters—for example, coupling constants, chemical shifts, nuclear Overhauser effect (NOE) signals, and relaxation times—that can be used in conformational studies; (3) the construction of models based on distance and/or dihedral angle information; and (4) the optimization and refinement of the proposed models by using various techniques, for example, distance geometry (DG), molecular mechanics energy minimization, and molecular dynamics with augmentations to include NMR-derived constraints. The comparison of theoretically derived results with other experiments is necessary to prove or disprove the initial assumption of the conformational distribution. The properties of peptides vary with salt concentration and pH. Binding affinities and conformations in solution are among the most important properties of peptides that determine activity and, ultimately, potency.