We present a combined computational and experimental study of the energy landscapes of cyclic tetra-alpha/beta-peptides. We have, performed discrete Path sampling calculations on a series of Cyclic tetra- alpha/beta-peptides to obtain the relative free energies, and barriers to interconversion of their conformers. The most stable conformers of cyclo-[(beta-Ala-Gly)(2)] contain all-trans peptide groups. The relative energies of the cis isomers and the cis-trans barriers are lower than in acyclic peptides but not as low as in the highly strained, cyclic alpha-peptides. For cyclic tetra-alpha/beta-peptides containing a single proline residue, of the type cyclo-[beta-Ala-Xaa-beta-Ala-Pro], the energy landscapes show that the most stable isomers containing cis and trans beta-Ala-Pro have similar free energies and are separated by barriers of approximately 15 kcal mol(-1). We show that the underlying energy landscapes of cyclo-[beta-Ala-Lys-beta-Ala-Pro] and cyclo-[beta-Ala-Ala-beta-Ala-Pro] are similar, allowing the substitution of the flexible side chain of Lys with Ala to reduce the computational demand Of our calculations. However, the steric bulk of the Val side chain in cyclo-[beta-Ala-Val-beta-Ala-Pro] affects the conformations of the ring; leading to significant differences between its energy landscape and that of cyclo-[beta-Ala-Lys-beta-Ala-Pro]. We have the cyclic peptide-cyclo-[beta-Ala-Lys-beta-Ala-Pro], and NMR spectroscopy shows the presence of conformers that interconvert slowly on the NMR time scale at temperatures up to 80 degrees C. Calculated circular dichroism (CD) spectra for the proposed major isomer of cyclo-[beta-Ala-Ala-beta-Ala-Pro] are in good agreement with the experimental spectra of cyclo-[beta-Ala-Lys-beta-Ala-Pro], suggesting that the Ala cyclic tetrapeptide is a viable Model for the Lys analogue.