A molecular mechanics force field for the cobalt corrinoids

A force field for the cobalt (III) corrinoids (derivatives of vitamin B₁₂) for use with a modified version of the molecular mechanics program 2(87) has been developed empirically around 19 cobalt corrinoid crystal structures. Bond lengths, bond angles and torsional angles are reproduced with r.m.s. differences of 0.01 Å, 2.4 °, and 4.2 °, respectively, within the standard deviation of the mean of these parameters found in the solid state. The axial ligand occupying the lower coordination site in the cobalamins, 5,6-dimethylbenzimidazole, is shown to have very limited rotational freedom and is constrained by the downward-pointing b and d propionamide side chains of the corrin ring. Strain-energy profiles for rotation of the side chains of the corrin ring show the existence of several local energy minima and this explains the observed variability in the orientations of these side chains in the solid state. The known change in conformation which occurs in the C ring when the e side chain is epimerized from the lower to the upper face of the corrin ring in cyano-13-epicobalamin is correctly predicted, provided the starting conformation of the C ring is unbiased. A study of cyano-8-epicobalamin indicates that an analogous conformational change does not occur in the B ring and the epimerized d side chain assumes an equatorial orientation relative to the corrin ring. Parameters for the Co---C bond in alkylcobalamins were developed and the structure of methyl- and adenosylcobalamin are accurately reproduced. An examination of the strain energy consequences of rotation of the adenosyl ligand about the Co---C bond identifies a number of low-energy conformations at least two of which, in which adenosyl lies over the “southern” and “eastern” portions of the corrin ring, respectively, have been previously deduced from NMR observations. Coordinated neopentyl in neopentylcobalamin is much more hindered to rotation about the Co---C bond and the lowest conformation finds two γ(C) atoms straddling the upwardly projecting C46 methyl group of the corrin.