The cyclic side chain of the amino acid proline confers unique conformational restraints on its backbone and side chain dihedral angles. This affects two equilibria-one at the backbone (cis/trans) and the other at the side chain (endo/exo). Substitutions on the proline ring impose additional steric and stereoelectronic effects that can further modulate both these equilibria, which in turn can also affect the backbone dihedral angle (ϕ, ψ) preferences. In this review, we have explored the conformational landscape of several termini capped mono-(2-, 3-, 4-, and 5-) substituted proline derivatives in the Cambridge Structural Database, correlating observed conformations with the nature of substituents and deciphering the underlying interactions for the observed structural biases. The impact of incorporating these derivatives within model peptides and proteins are also discussed for selected cases. Several of these substituents have been used to introduce bioorthogonal functionality and modulate structure-specific ligand recognition or used as spectroscopic probes. The incorporation of these diversely applicable functional groups, coupled with their ability to define an amino acid conformation via stereoelectronic effects, have a broad appeal among chemical biologists, molecular biophysicists, and medicinal chemists.
Keywords: Cis-trans; Collagen; Conformational restriction; Exo-endo; Proline; Substituted proline.