Medicinal Chemistry

The Electronic Structure and Mechanism of the Adenosylcobalamin-Dependent Bio-Processes as Determined by the MCSCF Method

Abstract

Tudor Spataru*

The CASSCF geometry optimization of the adenosylcobalamin cofactor dependent processes common models with 12 orbitals and 12 electrons in the active space has been performed. The MCSCF geometry optimization shows a strong HOMO-LUMO coupling during the CASSCF orbitals mixing process. The HOMO-LUMO coupling causes an electronic density transfer from the HOMO, which at the beginning of the optimization process is constituted from the substrate atoms orbitals, to the LUMO, which is constituted from the adenosylco(III)balamin structure atomic orbitals. The Co-C bond cleavage reaction is starting from the beginning of the geometry optimization process due to the intermolecular transferred electronic density from the substrates to the adenosylco(III)balamin cofactor compound. Then, the HOMO and LUMO of the calculated models are converting into a bonding and an antibonding pair of orbitals with a central atom plus σ-axial ligands orbitals contribution and with a corrin ring plus axial ligands orbitals contribution, respectively. The HOMO-LUMO mixing process in the CASSCF procedure causes the intermolecular charge transfer process that converts into intramolecular charge transfer process, which is increasing up to about 1e- at the Co-C bond cleavage distance. The substrates of the adenosylcobalamin cofactor dependent bio-processes from one side and the 5'- deoxy-5’-adenosyl radical from another side are permanently growing their direct interactions along with the Co-C bond rupture process up to a strong direct interaction at the Co-C bond cleavage distance. Evidently, this is allowing for a hydrogen atom transfer between them. Altogether, the total energy barrier of the hydrogen transfer reaction from the substrate to the 5'- deoxy-5’-adenosyl radical reaction, the CASSCF HOMO and LUMO surface orbitals of the substrate and 5'-adenosyl radical interaction common model before and after the hydrogen transfer and a strong Pseudo-Jahn-Teller effect for only direct reaction demonstrate that the hydrogen transfer is an irreversible tunneling process, which certainly leads to the final products. All these results are pointing out to the Co-C bond cleavage and hydrogen transfer from substrate to 5'- deoxy-5’-adenosyl ligand concerted reactions in full agreement with the experimental data.