Modeling the noncovalent interactions at the metabolite binding site in purine riboswitches

We present gas phase quantum chemical studies on the metabolite binding interactions in two important purine riboswitches, the adenine and guanine riboswitches, at the B3LYP/6-31G(d,p) level of theory. In order to gain insights into the strucutral basis of their discriminative abilities of regulating gene expression, the structural properties and binding energies for the gas phase optimized geometries of the metabolite bound binding pocket are analyzed and compared with their respective crystal geometries. Kitaura-Morokuma analysis has been carried out to calculate and decompose the interaction energy into various components. NBO and AIM analysis has been carried out to understand the strength and nature of binding of the individual aptamer bases with their respective purine metabolites. The Y74 base, U in case of adenine riboswitch and C in case of guanine riboswitch constitutes the only differentiating element between the two binding pockets. As expected, with W:W cis G:C74 interaction contributing more than 50% of the total binding energy, the interaction energy for metabolite binding as calculated for guanine (-46.43 Kcal/mol) is nearly double compared to the corresponding value for that of adenine (-24.73 Kcal/mol) in the crystal context. Variations in the optimized geometries for different models and comparison of relative contribution to metabolite binding involving four conserved bases reveal the possible role of U47:U51 W:H trans pair in the conformational transition of the riboswitch from the metabolite free to metabolite bound state. Our results are also indicative of significant contributions from stacking and magnesium ion interactions toward cooperativity effects in metabolite recognition.