Studies of 3D models for cyclopentapeptides (CPP's) employing only NMR spectroscopy encounter a serious problem. Because of conformer averaging, 3D structure(s) derived directly from NMR data may not correspond to the energy minimum (minima) with low relative conformational energy. At the same time, independent energy calculations can determine all low-energy conformers for the CPP backbone. The two approaches are compared in this study by results obtained for cyclo(d-Pro1-Ala2-Ala3-Ala4-Ala5). Contrary to the conclusion (predominance of the βII‘γ type conformer) of earlier NMR studies, independent energy calculations found a different family of low-energy 3D structures that are consistent both with the NMR data in DMSO and with the known X-ray data on CPP's. The preferable Ala4 conformations were found in the αR/αL regions suggesting studies of cyclo(d-Pro1-Ala2-Ala3-Aib4-Ala5) which was synthesized. Further NMR studies confirmed the results of the independent energy calculations. The independent energy ...