Puckering of 4-Fluoro-L-proline Isomers and 4,4-Difluoro-L-proline Influencing Conformation of Ornithine-free Gramicidin S

Ornithine-free Gramicidin S (1, cyclo(Val-Leu-Leu-D-Phe-Pro)2) is a good scaffold for studying β-turn and sheet structures. 4-Fluororide proline was incorporated into 1, and the resulting puckering of Pro was evaluated. Two geometric isomers, trans-4-fluoro-Pro and cis-4-fluoro-Pro, were incorporated into peptides 2 and 3, respectively. 4,4-Difluoro-Pro, which had no isomer, was incorporated into 4. The fluoro-analogues of 2–4 formed sheet and β-turn structures. The “up” forms (Cβ-endo and Cγ-exo) of Pro were found in 2, which is their first observation in Gramicidin S analogues. The “down” forms (Cβ-exo), which have been observed previously in GS analogues, were found in 3 and 4. Energy minimization indicated a 3–4% energy benefit in the “down” form.