Conformation of dioxopiperazines. III. Conformational-energy calculations and evaluation of specific forces contributing to the intramolecular dioxopiperazine-phenyl ring-ring folding in cyclo(glycyl-phenylalanyl)

Conformational energy calculations on cyclo(glycyl-L-phenylalanyl), c(Gly-Phe), were carried out by means of the semiempirical MO CNDO/2 method. They corroborated earlier experimental findings that in c(Gly-Phe) the conformations with an aromatic side-chain ring folded over the dioxopiperazine (DOP) ring contribute significantly to the overall equilibrium, provided that the empirical optimization of the DOP ring geometry, extracted from x-ray data, rather than that of the CNDO/2-derived data is used throughout the computations. Following these studies, more detailed calculations, based partly on CNDO/2-derived data and partly on experimental data, were carried out to clarify the question, which are the forces responsible for this ring-ring stacking? In contrast to early suggestions, it was found that the quadrupole-quadrupole and dispersion interactions mainly contribute to folded conformations of c(Gly-Phe). Some implications of this finding on devising force fields for molecular-mechanics calculations of peptides are briefly outlined.