New biochemical insights into the dynamics of water molecules at the GMP or IMP binding site of human GMPR enzyme: A molecular dynamics study

Human GMP reductase (hGMPR) enzyme is involved in a cellular metabolic pathway, converting GMP into IMP, and also it is an important target for anti-leukemic agents. Present computational investigations explain dynamical behavior of water molecules during the conformational transition process from GMP to IMP using molecular dynamics simulations. Residues at substrate-binding site of cancerous protein (PDB Id. 2C6Q) are mostly more dynamic in nature than the normal protein (PDB Id. 2BLE). Nineteen conserved water molecules are identified at the GMP/IMP binding site and are classified as (i) conserved stable dynamic and (ii) infrequent dynamic. Water molecules W11, W14, and W16 are classified as conserved stable dynamic due to their immobile character, whereas remaining water molecules (W1, W2, W3, W4, W5, W7, W8, W9, W10, W12, W13, W15, W17, W18, and W19) are infrequent with dynamic nature. Entrance or displacement of these infrequent water molecules at GMP/IMP sites may occur due to forward and backward movement of reference residues involving ligands. Four water molecules of hGMPR-I and nine water molecules of hGMPR-II are observed in repetitive transitions from GMP to IMP pathway, which indicates discrimination between two isoforms of hGMPRs. Water molecules in cancerous protein are more dynamic and unstable compared to normal protein. These water molecules execute rare dynamical events at GMP binding site and could assist in detailed understanding of conformational transitions that influence the hGMPR's biological functionality. The present study should be of interest to the experimental community engaged in leukemia research and drug discovery for CML cancer.