Conformational Preferences in Small Peptide Models: The Relevance of cis/trans-Conformations

The accurate description of cis/trans peptide structures is of fundamental relevance for the field of protein modeling and protein structure determination. A comprehensive conformational analysis of dipeptide model Ace-GlyNMe (1) has been carried out by using a combination of theoretical calculations and experimental (H-1 and C-13 NMR and NOESY) spectroscopic measurements to assess the relevance of cis-peptide conformers. NMR measurements in dimethyl sulfoxide (DMSO) solution and calculations employing a continuum solvation model both point to the extended trans,-trans conformer C5_tt as the global minimum. The cis-peptide structures C5_ct and C5_tc, with the N-or C-terminal amide group in cis-conformation, are observed separately and located 13.0 +/- 2 kJmol(-1) higher in energy. This is in close agreement with the theoretical prediction of around 12 kJmol(-1) in DMSO. The ability of common protein force fields to reproduce the energies of the cis-amide conformers C5_ct and C5_tc in 1 is limited, making these methods unsuitable for the description of cis-peptide structures in protein simulations