Helical Twists and β-Turns in Structures at Serine–Proline Sequences: Stabilization of cis-Proline and type VI β-turns via C–H/O interactions

Structures at serine-proline sites in proteins were analyzed using a combination of peptide synthesis with structural methods and bioinformatics analysis of the PDB. Dipeptides were synthesized with the proline derivative (2 S ,4 S )-(4-iodophenyl)hydroxyproline [hyp(4-I-Ph)]. The crystal structure of Boc-Ser-hyp(4-I-Ph)-OMe had two molecules in the unit cell. One molecule exhibited cis -proline and a type VIa2 β-turn (BcisD). The cis -proline conformation was stabilized by a C–H/O interaction between Pro C–Hα and the Ser side-chain oxygen. NMR data were consistent with stabilization of cis -proline by a C–H/O interaction in solution. The other crystallographically observed molecule had trans -Pro and both residues in the PPII conformation. Two conformations were observed in the crystal structure of Ac-Ser-hyp(4-I-Ph)-OMe, with Ser adopting PPII in one and the β conformation in the other, each with Pro in the δ conformation and trans -Pro. Structures at Ser-Pro sequences were further examined via bioinformatics analysis of the PDB and via DFT calculations. Ser–Pro versus Ala-Pro sequences were compared to identify bases for Ser stabilization of local structures. C–H/O interactions between the Ser side-chain Oγ and Pro C–Hα were observed in 45% of structures with Ser- cis - Pro in the PDB, with nearly all Ser- cis -Pro structures adopting a type VI β-turn. 53% of Ser- trans -Pro sequences exhibited main-chain C=O i •••H–N i +3 or C=O i •••H–N i +4 hydrogen bonds, with Ser as the i residue and Pro as the i +1 residue. These structures were overwhelmingly either type I β-turns or N-terminal capping motifs on α-helices or a 310-helices. These results indicate that Ser-Pro sequences are particularly potent in favoring these structures. In each, Ser is in either the PPII or β conformation, with the Ser Oγ capable of engaging in a hydrogen bond with the amide N–H of the i +2 (type I β-turn or 3 -helix; Ser χ1 t ) or i +3 (α-helix; Ser χ1 g+ ) residue. Non-proline cis amide bonds can also be stabilized by C–H/O interactions. ![Graphical Table of Contents][1] Graphical Table of Contents ### Competing Interest Statement The authors have declared no competing interest. [1]: pending:yes