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.