Theoretical studies of cyclic octapeptides from the marine ascidian Lissoclinum patella

A comparative theoretical study of oxazole and thiazole was carried out in order to evaluate the performance of several theoretical methods that might be useful in studies on the much larger patellamides (1-8), a family of cyclic octapeptides from the marine ascidian Lissoclinum patella. Several density functional theory (DFT) methods were included in this study and it was found that whilst all the functionals tested performed well, HCTH and B3LYP gave results that were better than those obtained at the Hartree-Fock level and equal to or better that the MP2 method but at reduced computational cost. As a result of this preliminary work the B3LYP functional was chosen and the 6-31G(d,p) basis selected for use in the patellamide study. This level of theory was also chosen for studies of the Cu2+ binding site in the patellamides with the SBKJC effective core potential basis. (Fig. 3772) Equilibrium geometries and energies were obtained for a number of conformers/rotamers of ascidiacyclamide (1) and patellamides A (2), C (4) and D (5) at the B3LYP/6-31G(d,p) level and were used to help rationalise the empirical observations that substitutional asymmetry appears to be responsible for determining the conformational (folding) preferences in these peptides. The results showed that the energy change on folding (DeltaEfolding) was positive for all four peptides but that the various substitutions significantly reduced the magnitude of DEfolding compared with the C2 symmetric 1. Desymmetrisation of the oxazoline rings in 2 gives rise to changes in the b-turn forming portions of the macrocycle, leading to improved folding at these positions. Alternatively, the local structure around the two thiazole ring containing regions can be altered by substitution at R1 and R3, leading to improved closure of the macrocycle outwith the beta-turn and improved pi-stacking between these moieties and shorter hydrogen bonding distances in other areas of the macrocycle.