Molecular Mechanisms of Caffeine Biological Effects. Computer Simulation of Competition with Adenosine for Binding Sites of Receptors

Caffeine is well known and widely used from ancient time. It is a biologically active substance with a broad activity spectrum. Caffeine (K) has influence on functions of proteins, nucleic acids and membranes. Its main pharmacological effect is central nervous system stimulation which is related to its acting as a concurrent antagonist of Adenosine (Ado) on adenosine receptors A1 and A2A. The aim of this work is to clarify molecular mechanism of this effect. The main question, that we raise and try to answer, using computer modeling is – «How comparatively small and practically rigid K molecule with limited possibilities to take part in strong non-bonded interactions can compete for binding sites with Ado molecule, which have more hydrogen bonding centers and noticeable conformational flexibility?» To obtain the answer, we have calculated interaction energy minima for molecules of K and Ado with the portions of the receptor transmembrane fragments responsible for Ado binding, using methods of molecular mechanics. It was found that the energy values in the deepest minima for K and Ado are close to each other. Consideration of geometrical properties of molecular models for complexes corresponding to these energy minima and for separate Ado molecule shows that both Ado and K form not more than three H bonds with the corresponding fragment of the receptor. Qualitative explanation for these results is given by formation of two intramolecular H-bonds in most probable conformations of Ado molecule, which limits the possibility of its interaction with the corresponding acceptor atoms of receptor fragments. Therefore, two different by the number of hydrophilic centers and by conformational possibilities molecules, turn out to be close from the point of view of energy of complex formation with the fragments of adenosine receptors.