CHAPTER 13: Experimental and Computational Approaches to the Study of Macrocycle Conformations in Solution

Cyclic peptides have undergone a renaissance in medicinal chemistry, as studies into structure–property relationships have revealed that passive cell permeability can be designed into synthetic cyclic peptide scaffolds when conformational factors are considered. The elucidation of cyclic peptide conformations in low-dielectric, membrane-mimicking solvents such as chloroform has therefore become an important tool for studying passive permeability in cyclic peptides, while aqueous conformational ensembles correlate both to target engagement and aqueous solubility. This chapter reviews a variety of NMR and computational techniques for the study of cyclic peptide conformations in solution, with a focus on the use of coupling constants to obtain dihedral information, NOESY- and ROESY spectra to obtain through-space distances, and residual dipolar couplings to obtain the relative orientation of bond vectors. Hydrogen–deuterium exchange and temperature shift methods are also discussed as tools for evaluating hydrogen bonding, and computational methods that employ NMR-based restraints are compared.