Molecular Modeling of a Hexacyclopeptide Dichotomin B Based on B3LYP, HF and ONIOM Methods: Comparison with Dichotomin A

Dichotomin B shows cell growth inhibitory activities against p-388 lymphocytic leukemia cells. However, its spatial conformation and the primary factors affecting its activity are not very clear. Here we optimize the primary structure of dichotomin B at the DFT (density functional theory) with B3LYP parameterization, HF (Hartree-Fock) and ONIOM (our own N- layered integrated molecular orbital and molecular mechanics) levels of theory. As a result, all the optimized geometries contain one beta-turn and two intramolecular hydrogen bonds which presumably maintain the steady spatial arrangements of dichotomin B in solid state and contribute to its activity, while there are two beta-turns and two intramolecular hydrogen bonds in the crystal structure of dichotomin A, which may be the reason that the activity of dichotomin A is higher than that of dichotomin B. In addition, the ¹³C chemical shifts of the three optimized geometries are calculated. We find that the structure obtained with HF/6-31G(d) method is the most similar to the experimental structure of dichotomin B. Furthermore, the RMS (root mean square) errors for ¹³C chemical shifts relative to TMS determined using the B3LYP hybrid functional with the 6- 311G(d,p) basis set are smaller than those determined using HF at this same basis set.