Abstract

A proposed molecular mechanism for the activation of the H2-receptor of histamine was simulated with ab initio calculations including geometry optimization with several basis sets. The system is modeled by a proton-relay chain produced by the binding of a histamine molecule to a receptor model consisting of an anionic anchoring site, and proton donor and acceptor sites. The anchoring of histamine cation at a negative receptor site is simulated by the interaction with a hydroxyl anion or by calculations on neutral histamine; the proton donor and acceptor sites are modeled by ammonium and ammonia groups, respectively. Results of the calculations reveal that a significant decrease in the barrier for the movement of the proton from the donor site to the N1 nitrogen in the imidazole portion of histamine occurs as a consequence of the neutralization of the side chain and the simultaneous interaction of the N3 nitrogen with the proton acceptor. An increase of the driving force for the proton transfer process is produced by these interactions, as observed from the relative energies of the initial and final steps of the charge relay. The barrier and the driving force depend on the nature of the proton acceptor site. This simulation of the receptor activation mechanism provides the basis for exploration of the partial receptor activation by molecules characterized as partial agonists and the lack of activation by molecules that act as antagonists on this receptor.