Resolving differences in substrate specificities between human and parasite phosphoribosyltransferases via analysis...

We herein review experimental and theoretical approaches widely applied to delineation of the differences in substrate specificities between human and parasite phosphoribosyltransferases (PRTases), the latter of which are key targets for treatment of diseases caused by parasites. Standard Molecular Dynamics (MD) simulations have been applied to determine why the human PRTase prefers guanine over xanthine, whereas the Tritrichomonas foetus enzyme exhibits only a slight preference. We analyze this problem with the aid of standard MD simulations, as well as constant-pH MD simulations. Comparison of results of the two approaches reveals substantial differences, e.g. several Asp and Glu residues in the parasite enzyme, and one Glu residue in the human enzyme, are predicted to be permanently or frequently protonated during constant-pH simulations, whereas standard MD simulations assume that these residues are always ionized. Most interesting is the observation of a large conformational change, leading to tighter binding of the ligand, observed in constant-pH MD simulations of the parasite PRTase complexed with XMP, and lack of such a change in the human enzyme complexed with XMP.