DFT CALCULATIONS FOR VITAMIN B12 COMPOUNDS AND REACTIONS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The vitamin B12 containing enzyme , methionine synthase, is one of the most important enzymes in the human body situated in essential metabolic pathways. Molecular orbital calculations on vitamin B12 compounds, called cobalamins , which are cobalt -corrin ring systems, are to be made to understand their chemical and biochemical properties. We have compared the PM3 semi-empirical method for the complete methylcobalamin structure ( 183 atoms, 506 electrons) with a DFT calculations at the B3LYP/LANL2DZ level for a model system of CH3-corrin Im (imidazole) (73 atoms, 274 electrons). Although PM3 geometry is close to that of the DFT calculations, it is clear that energies and molecular orbital contours are not even qualitatively correct for PM3 results. None of the previous DFT model calculations in the literature were made with the negatively charged phosphate containing side chain which would change the overall charge on the molecules. Most of our previous DFT calculations were made with the Gaussian ( 98 or 03) program on a single node computer and a single geometric optimization of the model compound could take more than two weeks ( 418 basis functions, 1097 primitive Gaussians). We now need to make DFT calculations on more complete model cobalamin systems which will require multiprocessor calculations and large amounts of memory , in order to correctly model geometry and bond dissociation energies of alkyl-cobalamins, NO-cobalamin, N2O-cobalamin , and other species, and Raman spectra, reduction potentials, and transition states in the enzymatic reactions and chemical reactions where the Co-C bond and NO-Co bonds are broken. These studies should help in understanding mechanisms at the active site of methionine synthase which uses methylcobalamin as a cofactor. Calculations will involve accurate solvation calculations and eventually QM/MM of the methylcobalamin active site of methionine synthase.