A molecular model for activation of a 5-hydroxytryptamine receptor.

The extension of a model proposed previously for molecular recognition at a serotonin (5-hydroxytryptamine (5-HT) ) receptor makes possible the formulation of a molecular mechanism of receptor activation. The activation mechanism proposed here is based on the changes induced in the drug and in a model receptor by the interaction mimicking the formation of a drug-receptor complex. This mechanism was simulated by quantum mechanical calculations of molecular interactions between 5-HT and a model for a receptor represented by an imidazolium-ammonia complex that serves as a proton transfer model (PTM). The movement of the proton in the PTM is promoted by the interaction with 5-HT, suggesting a process by which 5-HT can trigger the activation of the receptor. The elements of the activation mechanism revealed by the results of the simulation are: (a) the electrostatic alignment between the PTM and 5-HT, which guides the recognition of 5-HT by the PTM; (b) the contraction of the distance between the hydrogen bonded components of the PTM, induced by the interaction of 5-HT with the PTM, which leads to a decrease in the barrier to proton transfer in the PTM; (c) an additional decrease of the barrier to proton transfer produced by the negative electrostatic potential of 5-HT, which stabilizes the transition state; and (d) the increased preference for product over reactant in the interaction complex between 5-HT and the PTM, which constitutes a driving force for the proton transfer process. According to this model, compounds that activate the 5-HT receptor should bind in a mode that induces the changes described above in the PTM and thus triggers the proton transfer.