Hairpin formation promoted by the heterochiral dinipecotic acid segment: A DFT study

Conformational preferences for the turn and β‐hairpin structures of Ala‐based peptides [Ac‐Ala n ‐(R)‐Nip‐(S)‐Nip‐Ala n ‐X (n = 0–2; X = NHMe or NMe 2 )] containing nipecotic acid (Nip) residues were carried out using the density functional M06‐2X and the implicit solvation model SMD in CH 2 Cl 2 and/or water. The turn structure of the (R)‐Nip‐(S)‐Nip segment with a C 10 H‐bond between two terminal groups was found to be most preferred (populated at 98.9%) in CH 2 Cl 2 ; this structure is consistent with IR and 1 H NMR results. The stabilities of the β‐hairpins containing the (R)‐Nip‐(S)‐Nip segment as a turn motif relative to the extended structures increased with peptide sequence length. The relative strengths of the H‐bonds between the carbonyl oxygen and the amide hydrogen appeared to be responsible for stabilizing the turn and β‐hairpin structures in CH 2 Cl 2 . In addition, the (R)‐Nip‐(S)‐Nip segment exhibited the capability to be incorporated into one of the two β‐turn motifs of gramicidin S (GS). The structure of this GS derivative (GS‐Nip 2 ) was generally similar to the native peptide but was less hydrophobic and it is therefore expected to exhibit lower hemolytic activity; however, further experiments are needed to evaluate its antimicrobial activity. The structure of GS‐Nip 2 was somewhat more flexible than GS in solvents of higher polarity. Thus, our calculated results regarding the turn and β‐hairpin motifs of the (R)‐Nip‐(S)‐Nip segment indicate that this structure might be useful for the design of bioactive macrocyclic peptides containing β‐hairpin mimics as well as binding epitopes in protein–protein and protein–nucleic acid recognitions. © 2015 Wiley Periodicals, Inc. Biopolymers 103: 609–617, 2015.