Theoretical study on the interaction between dopamine and its receptor by ab initio molecular orbital calculation

Dopamine has been implicated in the function of a diverse set of central nervous system and peripheral functions. We theoretically evaluated the chemistry of interaction between dopamine and its receptor using ab initio molecular orbital calculation. First, we calculated the total energy of dopamine on either a protonated or deprotonated molecule at the meta- or para-position hydroxy group of the catechol ring, and then evaluated the hydrogen bond effect in these hydroxy groups. These results suggested that the meta-position hydroxy group was liable to be protonated, and subsequently deprotonated by a negatively charged receptor site. It was considered that proton flopping, which occurred within the receptor site via the meta-position hydroxy group, appeared to be essential for exerting the biological action of dopamine. On the other hand, the para-position hydroxy group of the catechol ring contributed to stabilization of a dopamine molecule at the receptor site through a hydrogen bond. Second, we showed that the side-chain amino group of dopamine was readily protonated and bound a negatively charged receptor site by coulomb interaction. Third, we calculated the highest occupied molecular orbital and lowest unoccupied molecular orbital to elucidate chemical reactivities of these functional groups on the electron level. From the molecular orbital contour maps, it was suggested that frontier orbital interaction was involved in the dopamine-receptor interaction, in which the meta- and para-position hydroxy groups may function as a proton acceptor and a proton donor, respectively. Considering these theoretical results together, we hereby propose a model of the dopamine-receptor interaction: (1) a protonation-deprotonation at the meta-position hydroxy group takes place, (2) the protonated side-chain amino group of dopamine binds to a negatively charged receptor site by an ionic bond, and (3) the para-position hydroxy group not only contributes to stabilization for dopamine binding but may also enhance the protonation-deprotonation at the meta-position through bond interaction along the pi-bond between OH and the benzene ring.