Theoretical studies on the interaction of modified pyrimidines and purines with purine riboswitch

Recent experimental study [S.D. Gilbert, S.J. Mediatore, R.T. Batey, Modified pyrimidine specifically bind the purine riboswitch, J. Am. Chem. Soc. 128 (2006) 14214-14215] demonstrated that the purine riboswitch could specifically bind some ligands other than purines such as amino-pyrimidines, and the authors proposed that the five-membered ring of purine was not required for recognition. To get insight into the interaction details, we used molecular docking method to investigate the interactions of a mutant form of guanine riboswitch with a series of amino-purines, amino-pyrimidines and imidazole derivatives, and employed molecular simulation method to study the dynamic behavior of the selected complexes. The calculation results reveal that (1) all the amino-purines and amino-pyrimidines bind in a same cavity composed of four nucleobases including U22, U47, U51 and U74, which is consistent with the experimental results, while the two imidazole derivatives adopt other binding modes; (2) the purines are engulfed within three-way junction motifs, but most pyrimidines only form two-way junctions with the riboswitch; (3) the number and position of amino substituents could seriously affect the binding of pyrimidines. As riboswitches are potentially excellent candidates for antibiotic therapeutics, these findings may be useful for understanding the range of compounds that riboswitch can specifically recognize.