Computational study of possible complexes of caffeine and adenosine with adenosine receptor fragments

Abstract Caffeine (CAF) is a biologically active substance with the broad function spectrum well-known from ancient times and widely used nowadays. The main pharmacological effect of CAF, stimulation of central nervous system, is due to its acting as a concurrent antagonist of Adenosine (Ado) on membrane proteins, namely, adenosine receptors A1 and A2a. In this work we study the atomic level mechanism of this effect. The main question that we try to answer using computer modeling is «How can comparatively small and practically rigid CAF molecule, with its limited possibilities to take part in sufficiently strong inter-molecular interactions, compete for binding sites with Ado molecule, which has more hydrogen bonding centers and significant conformational flexibility?» To approach this question we have calculated, using molecular mechanics (MM) method, the minima of interaction energy of CAF and Ado molecules with the fragments of transmembrane receptor domains participating in Ado binding. The MM computations revealed that the most probable conformations of separate Ado molecule correspond to the formation of two intra-molecular H bonds. This conclusion was confirmed at MP2/6-31G(d,p) and MP2/6-311++G(d,p) levels of the ab initio theory. It restricts the possibility of Ado interactions with hydrophilic amino acids of the receptor fragments. Thus, at the deepest minima of the interaction energy, both Ado and CAF form H bonds with no more than three amino-acid residues. The energy values at these minima are rather close to each other. Therefore, two molecules that are substantially different in the number of hydrophilic centers and in conformational possibilities turn out to be similar from the point of view of the energy of complex formation with adenosine receptor fragments.