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

摘要

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 Nlayered integrated molecular orbital and molecular mechanics) levels of theory. As a result, all the optimized geometries contain one β-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 β-turn 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.