Abstract

A histamine H2 receptor model was constructed based on the receptor sites previously proposed by Weinstein et al. [Mol. Pharmacol. 29:28-33 (1986)]. In this model, a glutamate or aspartate residue, simulated by a formate anion, is proposed both as the negative site at which the histamine cation is anchored to the receptor and as a proton-acceptor site. A proton-donor site, simulated by an ammonium cation, is proposed to model either a lysine, arginine, or histidine residue. The simulation of the activation mechanism of the histamine H2 receptor, inside the proposed receptor model, includes structure optimizations of stationary points and transition states with a split valence basis set. The proton movement from the proton donor site to the proton acceptor site, mediated by the imidazole ring of histamine, was found to be sequential in the potential energy surface. Results of the calculations reveal that both proton transfers are feasible from an energetical point of view. However, the proton movement from N(3) to the proton acceptor site has a higher energy of activation and, therefore, will be the rate-limiting step in the starting process that triggers the cascade of events that finally leads to a biological response. This model also provides a basis for explaining the molecular determinants of the pharmacological activity of N alpha-guanylhistamine. The structural properties of the guanidinium group allow N alpha-guanylhistamine to interact with the proposed receptor in two different modes. The proton-relay process, proposed as the trigger of the activation of the histamine H2 receptor, is likely to occur in only one of these binding modes. In the other case, N alpha-guanylhistamine acts as an antagonist because the barrier to proton transfer in this mode is too high. The partial agonism of N alpha-guanylhistamine is related to the ability of the drug to bind with the receptor in two different modes with similar affinity. An energetic analysis of the interaction between of ligand and the receptor model, including the energies of ligand desolvation, shows that histamine can compete with N alpha-guanylhistamine for the binding to the H2 receptor.