Crystal structures reveal that the sterically hindered pivaloyl‐cisProlyl amide bond is energetically frustrated

Abstract

AbstractBackgroundCisPro/transPro isomerism at the prolyl amide bond is a fundamental dynamism governing protein folding, structure, and functions. Since cisPro crystal structures are rare, the interactions influencing their structures are less understood, unlike transPro. Crystal data for the sterically hindered pivaloyl‐cisProlyl amide bond (2,2‐dimethyl‐1‐(1‐pyrrolidinyl)‐1‐propanone, Piv‐cisPro) were particularly lacking for decades. Here we introduce Piv‐Pro‐Xaa‐OMe dipeptides which crystallize with the elusive Piv‐cisPro (Xaa is Leu/Ile) and the abundant Piv‐transPro (Xaa is Gly/Phe) conformers.ResultsNatural bond orbital, quantum theory of atoms in molecules, and density functional theory calculations performed on these crystal structures and on the rotamers of the pivaloyl group reveal the presence of two constant n➔σ* interactions and a network of varying van der Waals interactions with unfavorable energies influencing this cisPro/transPro dynamism. Both conformers are hence energetically frustrated. The Piv‐cisPro amide bond distorts significantly to lower its energy by avoiding hard sphere clashes. Still, only in a narrow range of 12° of rotation along the CαPiv‐CβPiv bond, the Piv‐cisPro energies are relatively more favorable than Piv‐transPro. Piv‐cisPro crystallizes within this range.ConclusionsInteractions that constrain the CαPiv‐CβPiv bond within this 12° range can further stabilize Piv‐cisPro in crystals. Current results provide the first insights into interactions governing Piv‐Pro amide bond isomerism.