Abstract
Plasmodium deoxyguanylate pathways are an attractive area of investigation for future metabolic and drug discovery studies due to their unusual substrate specificities. We investigated the energetic contribution to thymidylate kinase substrate binding, and the forces underlying ligand recognition. The binding constant varied from 8 x 10(4) M-1 at 290 K to 6 x 10(4) M-1 at 310 K for dGMP, and from 16 x 10(4) M-1 at 290 K to 4 x 10(4) M-1 at 310 K for TMP. Delta C (p) was estimated as -1.75 kJ mol(-1) K-1 for TMP and +2 kJ mol(-1) K-1 for dGMP. In comparison with TMP, the binding of dGMP to PfTMK produced less favorable enthalpy change, positive or favorable entropic contribution at lower temperature, positive heat capacity change, negative , positive Delta S (other), higher total solvent-exposed surface area and more or less rigid body binding. These changes indicate unfavorable conditions for proper binding and lower conformational changes, and suboptimal structural reordering during dGMP binding.