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 centr al 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 tota l energy of dopamine on either a protonated or deprotonated molecule a t the meta- or para-position hydroxy group of the catechol ring, and t hen evaluated the hydrogen bond effect in these hydroxy groups. These results suggested that the meta-position hydroxy group was liable to b e protonated, and subsequently deprotonated by a negatively charged re ceptor site. It was considered that proton flopping, which occurred wi thin the receptor site via the meta-position hydroxy group, appeared t o be essential for exerting the biological action of dopamine. On the other hand, the para-position hydroxy group of the catechol ring contr ibuted to stabilization of a dopamine molecule at the receptor site th rough a hydrogen bond. Second, we showed that the side-chain amino gro up of dopamine was readily protonated and bound a negatively charged r eceptor 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 elec tron level. From the molecular orbital contour maps, it was suggested that frontier orbital interaction was involved in the dopamine-recepto r interaction, in which the meta- and para-position hydroxy groups may function as a proton acceptor and a proton donor, respectively. Consi dering these theoretical results together, we hereby propose a model o f the dopamine-receptor interaction: (1) a protonation-deprotonation a t 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 onl y contributes to stabilization for dopamine binding but may also enhan ce the protonation-deprotonation at the meta-position through bond int eraction along the pi-bond between OH and the benzene ring. (C) 1997 A cademic Press Limited.