When we write the set of brackets around a chemical species to represent a chemical concentration, it really represents a sum of probable chemical species that are grouped together. This is especially important when we consider the potential states of large protein molecules such as cellular receptors. In pharmacologic theory, we often characterize the active or inactive states of the receptor as initial quantities such as [R] and [R*]. This is convenient for mathematically manipulating these receptor states in order to derive information about how they behave in the presence of stimulating or inhibiting molecules such as agonists or antagonists, but conveys little about the underlying molecular species connected with these active and inactive states.
Even using specific and detailed molecular dynamic simulations, the meaning behind the [R] and [R*] receptor states becomes less clear when we explicitly model these states. Since there are a vast multitude of possible conformations, it becomes increasingly difficult to separate out those conformations that belong to the active or inactive receptor states. Ironically, this has brought us full circle to consider what [R] and [R*] represent as specific molecular species. The closer we are to understanding the details of these states from crystallographic structures, the further we are from understanding the molecular species that make up the active and inactive states.
Anyone who has truly studied pharmacologic theory and molecular modeling knows that we often wind up with this essential conundrum. Some have chosen particular molecular motions or interactions such as the breaking of a salt bridge or the twist or turn of a helix to describe what they think is the active receptor state. These descriptions may contain accurate descriptions of the active receptor state, but the fact that receptors exist in a sea of thermal noise and that activating drugs or ligands bind to their target receptors with only a 3-4 kcal/mol maximum energy difference and display different active molecular conformations suggest that we need a clearer on and off molecular switch for receptor activation.
These are not impossible physical constraints to accommodate in a biophysical molecular model for receptor activation (see - http://www.bio-balance.com/JMGM_article.pdf and http://www.bio-balance.com/GPCR_Activation.pdf ), but because receptors are complex molecular structures that exist in multiple domains, the teasing apart of the essential molecular signal is very difficult from both an experimental and theoretical perspective. This is particularly true if the biophysical models fail to accommodate major experimental findings such as the redox sensitivity of receptor systems or the reduction in desensitization by combining an antagonist with an agonist. A comprehensive molecular model for receptor activation should contain these findings.