Structural and Dynamical Impact of Water Molecules at Substrate- or Product-Binding Sites in Human GMPR Enzyme: A Study by Molecular Dynamics Simulations.

Human guanosine monophosphate reductase (hGMPR) enzyme maintains the intracellular balance between adenine and guanine nucleotide pools, and it is an excellent target for the design of isoform-specific antileukemic agents. In the present study, we have investigated solvation properties of substrate GMP or product inosine-5'-monophosphate (IMP)-binding pocket of hGMPR by employing molecular dynamics simulations on conformations A (substrate GMP), B [substrate GMP with cofactor nicotinamide adenine dinucleotide phosphate (NDP)], C (product IMP with cofactor NDP), and D (product IMP). Nineteen water sites are identified precisely; they are responsible for the catalytic activity of this site, control structural and dynamical integrity, and electronic consequences of GMP or IMP in the binding site of hGMPR. The water sites of category-1 (W1, W4, W5, W6, W13, and W15) in normal protein and category-2 (W2, W3, W7, W8, W10, W17, and W18) in cancerous protein are unique and stabilize the guanosine or inosine group of GMP or IMP for participation in the enzymatic reaction, whereas the remaining water centers either stabilize pentose sugar ribose or the phosphate group of GMP or IMP. Furthermore, water sites of category-4 (W11, W14, and W16) appear to be conserved in all conformations during the entire simulation. The GMP-binding site in cancerous protein 2C6Q is significantly expanded, and its dynamics are very different from normal protein 2BLE. Furthermore, unique interactions of GMP(N1)···W2···Asp129/Asn158, IMP(N1)···W3···Glu289, and IMP(O6)···W10···Ser270 might be used in a water mimic drug design for hGMPR-II. In this context, water finding probability, relative interaction energy () associated with water site W, entropy, and topologies of these three water sites are thermodynamically acceptable for the water displacement method by the modified ligand. Hence, their positions in the catalytic pocket may also facilitate future drug discovery for chronic myelogenous leukemia by the design of appropriately oriented chemical groups that may displace these water molecules to mimic their structural, electronic, and thermodynamic properties.