The Effect of a Protein Environment on the Proposed Activation Mechanism of the Histamine H2‐Receptor

Abstract

AbstractLack of information on the molecular structures of receptor proteins hampers the development of an understanding of their mechanisms. Small molecular models have served in the study of discrete details of such mechanisms, but receptor processes like recognition and activation take place in the protein environment of the receptor which may have a role in the process. To learn about the possible role of the protein environment in these mechanisms, we followed a heuristic approach in which models are used that range from small molecular complexes to macromolecular environments that model the receptors. The underlying assumption in such modelling is that similar elements of secondary structure, present in the model proteins as well as in the receptors, will make similar contributions to the molecular mechanism in which they function. We report the results of computational simulations of the activation mechanisms in a model protein environment used to study the effect of the protein structure on the proposed activation mechanism of the H2‐receptor of the neurotransmitter histamine. The Protein Data Bank was searched for a protein of known structure that could serve as a model for a macromolecular environment of the histamine H2‐receptor, based on a series of requirements defined by findings from our previous work on small molecular complexes modelling recognition and activation mechanisms in that receptor. The enzyme citrate synthase, E.C. 4.1.3.7, was found to contain the structural elements necessary for such a model. The activation mechanism simulated inside this protein consists of two proton transfer steps: one from the receptor to the neurotransmitter and another from it to a different site of the receptor. Quantum chemical methods were used to calculate the energetics of the proton transfers inside the protein structure represented as a collection of point charges and polarizable dipoles included in the Hamiltonian. The energetic contribution from polarization, as well as the interaction of the proton transfer system with the helix dipoles, is found to affect the proton transfer mechanism. The results suggest protein engineering approaches that can be used to modulate receptor activity by specific changes in the protein structure.